European Journal of Cardiovascular Medicine

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterized by chronic hyperglycemia due to insulin resistance, impaired insulin secretion, or a combination of both. The global prevalence of T2DM is increasing at an alarming rate, with approximately 537 million adults affected in 2021, and projections indicating a rise to 783 million by 2045 [1]. This rapid escalation poses significant public health challenges, primarily due to the long-term complications of diabetes, which include both microvascular and macrovascular damage.

Among the macrovascular complications, cardiovascular disease (CVD)—especially coronary artery disease (CAD)—is the leading cause of morbidity and mortality in individuals with T2DM. Diabetic patients are at markedly higher risk for CAD and acute coronary events such as myocardial infarction and often experience worse prognoses compared to non-diabetic individuals [2]. These risks necessitate early identification and aggressive management using statins, antiplatelet agents, and tight glycemic control to reduce cardiovascular burden [3,4].

On the microvascular front, diabetic retinopathy (DR) is one of the most prevalent and visually debilitating complications of T2DM. DR affects nearly 35% of the diabetic population globally, with 12% experiencing vision-threatening forms [5]. In India, DR has become a significant contributor to blindness, with the diabetic population expected to grow from 50.8 million in 2010 to 87 million by 2030 [6]. Notably, individuals with diabetes are approximately 25 times more likely to develop legal blindness compared to non-diabetics [7].

Diabetic Retinopathy and CAD, although affecting different vascular beds, share common pathophysiological mechanisms including endothelial dysfunction, inflammation, and accelerated atherosclerosis. These shared mechanisms have prompted interest in using DR as a non-invasive surrogate marker for CAD. Several studies have explored this relationship, yielding conflicting results—some report a strong correlation between DR severity and CAD risk [8,9], while others do not [10], possibly due to differences in study design, population heterogeneity, or unadjusted confounding variables.

To overcome these limitations, our study seeks to investigate the association between DR severity and CAD in T2DM patients using a well-characterized cohort, incorporating comprehensive cardiovascular risk profiling and multivariate regression analysis. While advanced imaging modalities such as coronary CT angiography and adipose tissue radiomics offer insights into CAD risk [11-14], they are often expensive and not routinely accessible. Retinal screening, by contrast, is affordable, widely available, and non-invasive. This study aims to determine whether DR severity can serve as a practical and reliable marker for predicting CAD in T2DM patients, thereby aiding in early cardiovascular risk stratification and management.

This analytical cross-sectional study was conducted in the Departments of Medicine and Cardiology at Sri Aurobindo Medical College and Postgraduate Institute (SAIMS), Indore. The study included adult patients aged >18 years with a confirmed diagnosis of both type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) who presented to the outpatient department (OPD), inpatient department (IPD), or emergency services during the defined study period. Prior to inclusion, ethical clearance was obtained from the Institutional Ethics Committee, and written informed consent was obtained from all participants.

The sample size was calculated using the standard formula n = Z² × p (1−p)/d², where Z = 1.96 (for 95% confidence), p = 0.09 (estimated prevalence of T2DM with CAD), and d = 0.05 (absolute error). This yielded a minimum required sample size of 126. Considering the annual admission load of more than 120 eligible patients in the relevant departments, a final sample of 126 patients was recruited consecutively during the study period.

Inclusion and Exclusion Criteria

The study population comprised patients aged 18 years and above who had been diagnosed with both T2DM and CAD, confirmed through clinical history, relevant laboratory tests, electrocardiography (ECG), two-dimensional echocardiography (2D ECHO), and coronary angiography (CAG). Patients who refused consent or had comorbid chronic conditions that could confound the interpretation of hypoalbuminemia or retinal and cardiac status—such as chronic liver disease, chronic kidney disease, nephrotic syndrome, protein-losing enteropathy, or chronic malnutrition—were excluded.

All patients underwent detailed clinical evaluation, including history-taking and systemic examination. Fundus examination was performed using indirect ophthalmoscopy to determine the presence and severity of diabetic retinopathy (DR). Based on fundoscopic findings, DR was categorized into no retinopathy, non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR).

Standardized laboratory investigations were conducted for all patients and included complete blood count (CBC), fasting blood sugar (FBS), postprandial blood sugar (PPBS), glycated hemoglobin (HbA1c), lipid profile (total cholesterol, HDL, LDL, triglycerides), renal function tests (urea and creatinine), liver function tests (serum bilirubin, SGOT, SGPT), serum electrolytes, and cardiac enzymes such as troponin I, troponin T, and CPK-MB. Imaging studies such as ultrasonography of the abdomen and echocardiography were also performed where indicated.

To confirm and stratify coronary artery disease, all patients underwent coronary angiography, which served as the definitive diagnostic modality. In addition, supportive cardiac assessments were conducted using a 12-lead electrocardiogram (ECG) and two-dimensional (2D) echocardiography. The ECG was systematically analyzed for rate, rhythm, electrical axis, P wave morphology, PR interval, QRS complex duration and morphology, ST segment deviations, and T wave abnormalities. Specific abnormalities were defined as follows: T wave inversion of ≥1 mm in depth in two or more contiguous leads; QRS duration exceeding 120 milliseconds; ST-segment elevation or depression of ≥1 mm in two or more contiguous leads; prolonged PR interval >200 milliseconds; and QTc interval >440 milliseconds in men and >460 milliseconds in women. Additionally, 2D echocardiography was performed to evaluate cardiac structure and function, including assessment of left ventricular systolic function (ejection fraction), diastolic function, and the presence of structural changes such as left ventricular hypertrophy (LVH).

All relevant demographic, clinical, biochemical, and imaging data were recorded in a pre-structured proforma. Laboratory values and imaging findings were transcribed directly from institutional records to ensure consistency and accuracy.

Statistical Analyses

The data were compiled in Microsoft Excel 2010 and analyzed using SPSS 26.0 software. Descriptive statistics were used to present continuous variables as mean ± standard deviation (SD), while categorical variables were expressed as frequencies and percentages. Associations between the severity of diabetic

This study enrolled a total of 126 patients with type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR). The mean age of the study population was 58.23 ± 8.15 years. The majority of patients (50%, n=63) were in the 51–60 year age group. There was a male predominance, with 83 males (65.9%) and 43 females (34.1%). The mean duration of diabetes was 12.5 years. [Table 1]

Table 1. Distribution of Patients by Age and Retinopathy Severity (N=126)

* P<0.05 is considered statistically significant; Pearson Chi Square

Figure 1 highlights an age-related increase in diabetic retinopathy (DR) severity among 126 T2DM patients. Mild NPDR was seen in younger patients (18–50 years), while older groups (61–80 years) had more severe forms, including PDR. The 51–60 age group showed a transitional pattern. Statistically significant associations between age and DR severity were found in the 41–50, 61–70, and 71–80 groups (p<0.05), emphasizing the need for regular retinal screening in older diabetics.

Figure 1. Age-wise Distribution of Diabetic Retinopathy Severity

Table 2 shows that diabetic retinopathy (DR) severity increases with longer diabetes duration in 126 T2DM patients. Among those with diabetes ≤5 years, 85% had mild NPDR and only 15% had PDR, showing a significant association with milder DR (p < 0.001). In the 6–10 years group, DR severity was more varied and not statistically significant (p = 0.613). In patients with >10 years of diabetes, severe NPDR and PDR predominated, but this group also lacked a significant association (p = 0.723), possibly due to variability. Overall, longer diabetes duration aligns with more severe DR, but only early duration (≤5 years) shows a significant link with milder forms.

Table 2. Distribution of Patients by Duration of Diabetes and Retinopathy Severity (N = 126)

* P<0.05 is considered statistically significant; Pearson Chi Square

Table 3 illustrates the relationship between total cholesterol levels and diabetic retinopathy (DR) severity in 126 T2DM patients. Among those with cholesterol <200 mg/dL (n=80), 35% had mild NPDR, and only 22.5% had PDR, showing a statistically significant association with milder DR (p = 0.030). In contrast, patients with cholesterol >200 mg/dL (n=46) showed a higher prevalence of severe NPDR (30.4%) and PDR (34.8%), though the association was not statistically significant (p = 0.712). These results suggest that lower cholesterol levels may be linked to less severe DR, highlighting the importance of lipid control in diabetic care.

Table 3. Distribution of Patients by Cholesterol Levels and Retinopathy Severity (N = 126)

Table 4 highlights the association between glycemic control (HbA1c levels) and diabetic retinopathy (DR) severity in 126 patients. Among those with HbA1c levels between 6.5–8.5% (n=60), over half (51.7%) had mild NPDR, and only 11.7% had PDR, showing a statistically significant correlation with milder DR (p < 0.001). In contrast, among patients with HbA1c >8.5% (n=66), a higher proportion exhibited severe NPDR (24.2%) and PDR (40.9%), though this distribution was not statistically significant (p = 0.510). These findings emphasize that moderate glycemic control is significantly associated with less severe DR, while poor control is linked with advanced retinopathy, albeit potentially influenced by other confounding factors such as disease duration and comorbidities.

Table 4. Distribution of Patients by HbA1c Levels and Retinopathy Severity (N = 126)

Figure 2 demonstrates a clear inverse relationship between glycemic control (HbA1c levels) and the severity of diabetic retinopathy (DR) among 126 patients. In those with moderate control (HbA1c 6.5– 8.5%), the majority (51.7%) had mild NPDR, with only 28.4% showing advanced DR (severe NPDR or PDR). In contrast, among patients with poor control (HbA1c >8.5%), only 12.1% had mild NPDR, while 65.1% had advanced DR. These findings highlight that poorer glycemic control is significantly associated with more severe retinopathy. The data reinforce the importance of maintaining HbA1c below 8.5% to reduce the risk of vision-threatening retinal complications.

Figure 2. Correlation of HbA1c levels with Diabetic retinopathy severity

Table 5 highlights a significant association between mild non-proliferative diabetic retinopathy (NPDR) and cardiac changes (p = 0.001), suggesting that early retinal microvascular damage may coincide with subclinical cardiovascular involvement. This underlines the importance of initiating cardiac evaluation even at the early stages of diabetic retinopathy. Although moderate and severe NPDR, as well as proliferative diabetic retinopathy (PDR), showed higher proportions of cardiac changes, these associations were not statistically significant, possibly due to the influence of confounding factors like hypertension and hyperlipidemia. Furthermore, multivariate regression analysis identified DR severity, elevated cholesterol, and hypertension as independent predictors of cardiac abnormalities. These findings reinforce the concept of a shared pathophysiological basis between diabetic microvascular and macrovascular complications and emphasize the need for integrated cardiovascular risk assessment in patients with any degree of diabetic retinopathy.

Table 5. Distribution of Patients by Retinopathy Severity and Cardiac Changes (N = 126)

Electrocardiographic analysis revealed a significant association between diabetic retinopathy (DR) severity and specific structural cardiac abnormalities. Notably, left axis deviation (LAD) (p = 0.012) and left ventricular hypertrophy (LVH) (p = 0.002) were significantly more prevalent in patients with proliferative diabetic retinopathy (PDR), where each was observed in 40% of cases. This indicates that advanced stages of DR are linked with a higher burden of underlying myocardial stress and remodeling. In contrast, other ECG abnormalities—including arrhythmias, QRS I changes, ST-segment alterations, T wave anomalies, and left bundle branch block (LBBB)—did not show statistically significant associations with DR severity. These findings suggest that LAD and LVH may serve as important electrocardiographic markers for cardiac involvement in patients with advanced DR, reinforcing the necessity of integrated cardiovascular evaluation in this high-risk population.

Table 6. Distribution of ECG Abnormalities by Retinopathy Severity (N = 126)

Multivariate logistic regression analysis identified severe diabetic retinopathy (OR = 2.5), diabetes duration >10 years (OR = 3.1), and HbA1c >8.5% (OR = 2.8) as independent predictors of cardiac changes. All predictors were statistically significant. Variance inflation factor (VIF) values were below 5, confirming no multicollinearity and ensuring model reliability. These findings highlight the strong association between prolonged poor glycemic control, advanced DR, and increased cardiovascular risk.

This analytical cross-sectional study involving 126 patients with diabetic retinopathy (DR) revealed several significant associations between retinopathy severity and various demographic, clinical, and biochemical parameters. The mean age of the study population was 58.23 ± 8.15 years, with the majority falling in the 51–60 years age range. A higher prevalence of proliferative diabetic retinopathy (PDR) was observed in individuals aged over 70 years. Age demonstrated a significant correlation with DR severity (p<0.001), which could be attributed to cumulative glycemic burden over time. Comparable trends were noted in the study by Lingineni VB et al. [1] who reported mean age as 57.13 ± 8.51 years and Bamashmus et al. [15], where the average age was slightly lower at 54.4 years, and over half of the patients had diabetes for more than a decade, supporting the notion that DR progression worsens with age and disease duration.

A strong association was observed between duration of diabetes and DR severity. Among the 76 patients with diabetes duration >10 years, 25 had severe NPDR and 35 had PDR, a statistically significant trend (p<0.001), affirming that chronic hyperglycemia remains a key contributor to microvascular retinal. changes. Similar findings were reflected in previous done by Lingineni VB et al. [1] and Bamashmus et al. [15], emphasizing the role of long-standing diabetes in exacerbating retinal damage.

Our study also identified a significant correlation between cholesterol levels and DR severity. Of the 46 patients with total cholesterol >200 mg/dL, 14 (30.4%) had severe NPDR and 16 (34.8%) had PDR (p=0.033). These findings align with the study done by Lingineni VB et al. [1] and van Leiden HA et al. [16], which identified elevated total cholesterol and triglycerides as independent risk factors for retinopathy, highlighting the potential benefit of lipid-lowering interventions in slowing DR progression.

Regarding glycemic control, 66 patients had HbA1c levels >8.5%, and among them, 16 had severe NPDR and 27 had PDR. In contrast, among patients with HbA1c between 6.5–8.5%, over half had only mild NPDR, and advanced retinopathy was seen in fewer cases. This correlation was statistically significant (p<0.001), corroborating Henricsson et al. [17] and Lingineni VB et al. [1], who established that both the duration of diabetes and poor glycemic control, as indicated by HbA1c levels, are strong predictors of DR. Pathophysiologically, chronic hyperglycemia promotes oxidative stress, endothelial dysfunction, and inflammatory cascades—mediated in part by VEGF—which collectively accelerate the development of advanced retinal lesions [18].

Electrocardiographic (ECG) changes were noted in 42 patients (33.3%), with a progressive increase from 23.3% in mild NPDR to 70% in PDR, indicating a strong association between DR severity and subclinical cardiovascular changes. Notably, no significant gender difference was observed in the distribution of ECG changes. This mirrors the findings of Lingineni VB et al. [1], Eid M et al. [2] and Mohammad et al. [19], who noted a link between DR severity and cardiac autonomic neuropathy, suggesting that DR, particularly in its advanced stages, may be a surrogate marker for systemic vascular dysfunction, including subclinical cardiac involvement.

Hypertension, present in 29 patients, was significantly associated with both DR severity and cardiac changes, with 21 of these hypertensive patients (72%) showing ECG abnormalities (p<0.001). This supports the Lingineni VB et al. [1] and UKPDS:23 findings [20], which reported elevated cardiovascular risk in diabetic patients with hypertension. These findings suggest the need for strict blood pressure control as part of comprehensive DR and cardiovascular risk management.

While tobacco use was reported in 36 participants, there was no significant association between smoking and DR severity or ECG changes (p>0.05). This parallels findings from the Chennai Urban Population Study (CUPS) by Mohan V et al. [21] and Lingineni VB et al. [1], which also reported a lack of significant correlation between smoking and CAD in their cohort. The limited sample size or lack of detailed smoking history may account for the absence of a statistically significant effect in our study.

A family history of CAD also did not show a meaningful association with DR or cardiac findings (p>0.05), in contrast to the findings of Lingineni VB et al. [1] and Yarnell et al. [22], possibly due to genetic diversity, sample variability, or underreporting in our study population.

Our findings reinforce the observations from the study done by Lingineni VB et al. [1] and van Leiden HA et al. [16], which showed that retinopathy prevalence increases with worsening glycemic and lipid profiles, as well as elevated blood pressure and BMI. Although BMI was not specifically evaluated in our study, these factors are recognized contributors to DR progression. Likewise, Henricsson et al. [17] demonstrated in their 10-year follow-up that elevated LDL cholesterol and triglycerides are associated with a higher risk of DR worsening, supporting the benefit of long-term lipid control.

The association between DR and cardiovascular risk is also supported by the study by Mohammad et al. [19], indicating that patients with advanced DR often exhibit signs of cardiac autonomic dysfunction. This further highlights the need for cardiovascular screening in patients with severe retinopathy.

In summary, this study highlights that poor glycemic control (HbA1c >8.5%), longer diabetes duration, high cholesterol levels, and older age are significantly associated with increased severity of diabetic retinopathy (DR). Patients with better glycemic control (HbA1c 6.5–8.5%) were more likely to have milder forms of DR, emphasizing the importance of strict metabolic control and routine eye examinations. Additionally, the strong association between advanced DR and cardiac abnormalities suggests the need for integrated cardiovascular risk management in diabetic patients.

However, as a single-center cross-sectional study with a limited sample size (n=126), causality cannot be established, and generalizability is limited. Recall bias and unmeasured confounders like BMI, diet, and physical activity may also have influenced the results. Future longitudinal and multicenter studies are warranted to confirm these findings and explore the impact of targeted interventions, including lifestyle modifications and pharmacologic therapies, on DR progression and associated cardiovascular risks.

This study highlights a significant association between diabetic retinopathy (DR) and cardiac changes in patients with type 2 diabetes mellitus (T2DM). DR, beyond being a microvascular ocular complication, serves as a potential marker of systemic vascular dysfunction. A high prevalence of hypertension, dyslipidemia, and poor glycemic control among patients with DR further emphasizes the cumulative cardiovascular risk in this population. The cardiac abnormalities observed, likely influenced by prolonged diabetes duration and elevated lipid levels, suggest that DR may be an independent predictor of coronary artery disease (CAD). These findings underscore the importance of incorporating cardiovascular assessment into the routine evaluation of patients with DR. Early identification of cardiac risk and comprehensive management strategies—encompassing glycemic optimization, lipid control, and blood pressure regulation—are essential to mitigate long-term morbidity. Ultimately, DR should be recognized as a clinical indicator warranting vigilant cardiovascular surveillance in diabetic individuals to prevent further systemic complications.

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