European Journal of Cardiovascular Medicine

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycaemia resulting from insufficient insulin production, insulin resistance, or a combination of both [1]. It is a major global health concern with an estimated prevalence of 9.3%, affecting approximately 463 million individuals worldwide. Projections suggest that this number will increase to 578 million (10.2%) by 2030. In India, the prevalence is approximately 8.9% [1, 2]. A significant challenge in diabetes management is the delayed diagnosis due to a latent phase between the initial onset of hyperglycaemia and clinical identification, which can last between 4 to 7 years. Many cases remain undiagnosed, indicating that the known prevalence represents only the tip of the iceberg. If left untreated, chronic hyperglycaemia significantly increases the risk of developing severe microvascular complications, and in some instances, patients present with macrovascular complications at the time of diagnosis [3]. Among the most commonly observed microvascular complications are diabetic retinopathy, nephropathy, and neuropathy. In India, there is an increasing trend of newly diagnosed diabetes cases exhibiting these complications. Early identification and intervention play a crucial role in preventing disease progression, thus reducing morbidity and mortality. A deeper understanding of the intricate relationship between diabetes, microvascular complications, and the importance of early detection could lead to the development of improved preventive and therapeutic approaches.

Diabetic retinopathy is a well-documented microvascular complication frequently observed in newly diagnosed diabetes mellitus cases [3]. Globally, the prevalence of diabetic retinopathy among individuals with diabetes is reported to be 22.27%, with approximately 6.17% experiencing sight-threatening complications. In India, the reported prevalence of diabetic retinopathy stands at 17.6% [4], with rates ranging from 35% to 50% among newly diagnosed type 2 diabetes mellitus cases [4,5]. Diabetic retinopathy remains the leading cause of vision impairment and blindness among the diabetic population. The pathophysiology of diabetic retinopathy involves chronic hyperglycaemia, which leads to damage in the retinal microvasculature, resulting in increased vascular permeability, microaneurysm formation, hemorrhages, and ultimately, neovascularization in advanced stages. Studies have indicated that patients with diabetic retinopathy tend to have significantly elevated HbA1c levels compared to those without the condition, highlighting a strong correlation between HbA1c levels and disease severity. This association underscores the importance of strict glycaemic control in reducing the risk of developing diabetic retinopathy. Routine screening and timely intervention are essential for preventing visual loss and improving long-term patient outcomes [6]. Poor glycaemic control is a primary driver in the onset and progression of microvascular complications, including diabetic retinopathy. Apart from hyperglycaemia, additional factors such as the duration of diabetes, obesity, hypertension, and dyslipidaemia have also been found to influence the development of these complications. Several studies [7, 8] have demonstrated that HbA1c serves as a reliable marker for assessing long-term glycaemic control and correlates with the severity of diabetes. Despite these findings, there is limited comprehensive data exploring the precise relationship between HbA1c levels and the progression of microvascular complications, particularly in the population of Bihar. Furthermore, the interplay between diabetic retinopathy, nephropathy, and neuropathy remains inadequately investigated. Understanding these interconnections could help develop targeted strategies for early diagnosis and effective management of diabetes-related complications. This study aims to evaluate the association between serum HbA1c levels and the severity of diabetic retinopathy in type II diabetes mellitus patients. By analyzing the clinical profile of diabetic retinopathy and its correlation with HbA1c levels, we seek to identify key factors influencing disease progression and establish early interventions that could mitigate the severity of vision-threatening and life-threatening complications related to diabetes. The findings from this study could contribute to better screening strategies, patient education, and treatment protocols, ultimately leading to improved clinical outcomes for individuals with diabetes.

This prospective observational clinical study was conducted on patients diagnosed with type II diabetes mellitus at the Department of Ophthalmology, Government Medical College and Hospital, Bettiah, Bihar, India. The study involved a cohort of one hundred patients. The individuals were selected through a randomization process. Prior to participation, written informed consent was obtained from all patients. A comprehensive ocular examination and detailed systemic history were recorded, including the presence of any pre-existing non-diabetic retinopathy, maculopathy, non-diabetic renal disorders, prior laser photocoagulation therapy, and pre-existing neuropathy.

Ophthalmic Evaluation

The ophthalmic assessment included the measurement of best-corrected visual acuity (BCVA) using a Snellen chart for distant vision and a Jaeger chart for near vision. Intraocular pressure was measured using a Goldmann applanation tonometer. The anterior segment of the eye was evaluated with a slit-lamp biomicroscope. For a detailed fundus examination, pupils were dilated using topical 2.5% phenylephrine and 0.5% tropicamide, administered at 10-15 minute intervals with punctal occlusion to minimize systemic absorption. A dilated fundus examination was then performed using an indirect ophthalmoscope with a 20D lens.

Inclusion Criteria:

1. Patients diagnosed with type II diabetes mellitus.
2. Individuals aged 31 years and above.
3. Patients with documented HbA1c levels.
4. Patients diagnosed with diabetic retinopathy based on ophthalmologic evaluation.
5. Individuals who provided informed consent to participate in the study.

Exclusion Criteria:

1. Patients with type I diabetes mellitus.
2. Individuals with a history of ocular diseases unrelated to diabetic retinopathy (e.g., glaucoma, retinal detachment, or uveitis).
3. Patients with a history of ocular surgeries that could influence retinal changes.
4. Pregnant women or individuals with gestational diabetes mellitus.
5. Patients with systemic conditions that could affect HbA1c levels, such as chronic kidney disease or haematological disorders.
6. Individuals on long-term steroid therapy or other medications that significantly impact blood glucose levels.

Data collection involved retrieving demographic and clinical parameters. Demographic data included age and gender, while clinical data covered variables such as the duration of diabetes, age at onset of diabetes, glycaemic control, the use of anti-diabetic drugs, obesity, and diabetes-related complications such as neuropathy and nephropathy. The severity of diabetic retinopathy (DR) was classified into mild non-proliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR, and proliferative diabetic retinopathy (PDR) according to the International Clinical Diabetic Retinopathy Disease Severity Scale. According to the guidelines provided by the National Institute for Clinical Excellence, a normal weight is defined by a body mass index (BMI) between 18.5 and 24.9 kg/m². Individuals with a BMI ranging from 25 to 29.9 kg/m² are classified as overweight, while those with a BMI of 30 kg/m² or higher are categorized as obese.

Laboratory Investigations

All patients meeting the inclusion criteria underwent HbA1c level estimation. A 3 ml blood sample was drawn from the peripheral vein and sent to the pathology laboratory for analysis. Based on HbA1c levels, patients were categorized into the following groups:

• Good Control: HbA1c < 7%
• Poor Control: HbA1c between 7% to 9%
• Very Poor Control: HbA1c > 9%

All collected data were systematically recorded in a pre-designed proforma, and a master chart was created to analyze the relationship between glycosylated hemoglobin levels and the severity of diabetic retinopathy.

Statistical Analysis: The collected data was organized into a table using Microsoft Excel 2019. Next, the data was transferred to GraphPad version 8.4.3 for further statistical analysis. Frequencies and percentages were calculated for all variables under study. Cross-tabulation analyses were conducted using the chi-square test, while comparisons between groups were examined using independent t-tests and analysis of variance (ANOVA). A P-value of less than 0.05 was considered statistically significant.

The study examined the demographic characteristics and clinical parameters of diabetic patients to assess the relationship between HbA1c levels and the severity of diabetic retinopathy (Table 1). The majority of patients were in the age group of 40.1 to 50 years (30%), followed by those older than 60 years (27%). A smaller percentage fell into the 31 to 40 years (21%) and 50.1 to 60 years (22%) age groups. The mean age of the study group was 52.23±11.34 years. Males represented a larger portion of the study population, comprising 72%, while females accounted for 28%. In terms of the duration of diabetes, most patients had lived with the condition for 10.1 to 20 years (35%) or for more than 20 years (34%). Meanwhile, 31% had diabetes for a shorter duration of 1 to 10 years. Regarding glycaemic control, a significant number of patients displayed poor control, with 48% having HbA1c levels between 7% and 9%, and 35% exhibiting very poor control (HbA1c > 9%). Only 17% of the patients achieved good glycaemic control, with HbA1c levels below 7%.  Oral hypoglycaemic agents were used by 52 % of participants, while 48 % were on insulin alone or in combination with other drugs. Concerning body mass index (BMI), a notable proportion of patients were classified as overweight (34%) or obese (45%), with only 21% maintaining a normal BMI.

Table 1: Showing the different demographic profiles of the patients of both groups.

The study also examined the prevalence of diabetic complications among the patients (Table 2). Neuropathy was present in only 12% of the patients, while the remaining 88% did not show any signs of this complication. Similarly, nephropathy was observed in 17% of the cases, whereas 83% of the patients did not exhibit any kidney-related complications. Macular edema was present in 39% of the patients, while 61% did not have this condition. Regarding diabetic retinopathy, the severity varied among the affected individuals. Mild non-proliferative diabetic retinopathy (NPDR) was the most common, observed in 40% of the patients. Moderate NPDR was seen in 26%, while severe NPDR was found in only 6%. A significant proportion of patients, about 28%, had proliferative diabetic retinopathy (PDR), indicating advanced disease progression.

Table 2: Showing the prevalence of diabetic complications

The study analyzed the association between the severity of diabetic retinopathy and various demographic and clinical variables (Table 3). Age did not show a significant correlation with the severity of retinopathy (p=0.828). Patients across all age groups were affected, with the highest prevalence of proliferative diabetic retinopathy (PDR) observed in those aged 40.1-50 years (10%) and more than 60 years (5%). Similarly, gender was not significantly associated with the severity of retinopathy (p=0.592), although a higher proportion of males had mild NPDR (31%) and proliferative DR (18%) compared to females, where these conditions were observed in 9% and 10% of cases, respectively. The duration of diabetes mellitus also did not show a statistically significant association with retinopathy severity (p=0.178). However, patients with a longer duration of diabetes (more than 20 years) had a higher prevalence of PDR (15%) compared to those with a shorter duration. Glycemic control, as measured by HbA1c levels, was not significantly correlated with the severity of retinopathy (p=0.694). However, the majority of patients with PDR had poor (10%) or very poor (14%) glycemic control, whereas those with good control were mostly found in the mild NPDR category (9%). A significant association was found between the severity of retinopathy and the type of anti-diabetic medication used (p=0.044). Patients using insulin, either alone or in combination with oral hypoglycemic agents, had a higher prevalence of PDR (17%) compared to those on oral medications alone (11%). In terms of body mass index (BMI), no significant association was observed (p=0.212), though obese individuals had a higher prevalence of PDR (14%) compared to overweight (8%) and normal-weight individuals (6%). These findings indicate that while age, gender, duration of diabetes, HbA1c levels, and BMI were not significantly associated with the severity of diabetic retinopathy, the use of insulin therapy was found to have a statistically significant correlation.

Table 3: Showing the association between severity of retinopathy and other variables parameters.

[# Statistically Significant]

The study also examined the association between the severity of diabetic retinopathy and the presence of other complications (Table 4). Neuropathy was observed across different stages of retinopathy, but no statistically significant association was found (p=0.559). Among patients with mild non-proliferative diabetic retinopathy (NPDR), neuropathy was present in 3%, while it was observed in 5% of those with moderate NPDR, 1% of those with severe NPDR, and 3% of patients with proliferative diabetic retinopathy (PDR). The majority of patients in all groups did not exhibit neuropathy. Similarly, nephropathy did not show a statistically significant association with the severity of diabetic retinopathy (p=0.292). It was present in 4% of patients with mild NPDR, 7% with moderate NPDR, 1% with severe NPDR, and 5% with PDR. The majority of patients with all stages of retinopathy did not exhibit nephropathy. However, a significant association was found between macular edema and the severity of diabetic retinopathy (p=0.002). Among patients with mild NPDR, 8% had macular edema, whereas 12% of those with moderate NPDR, 6% of those with severe NPDR, and 5% of those with PDR also exhibited this complication. In contrast, macular edema was absent in 31% of patients with mild NPDR, 13% with moderate NPDR, 1% with severe NPDR, and 16% with PDR. These findings suggest that while neuropathy and nephropathy were not significantly associated with the severity of diabetic retinopathy, macular edema showed a strong correlation, indicating its potential role in the progression of retinal damage in diabetic patients.

Table 4: Showing the association between severity of retinopathy and the presence of other complications.

[# Statistically Significant]

The prevalence of type 2 diabetes mellitus is projected to increase by 2030. Diabetes is a medical disorder that is closely linked to many consequences, including both microvascular and macrovascular problems. Microvascular problems encompass retinopathy, nephropathy, and neuropathy, whereas macrovascular complications include ischemic heart disease, peripheral vascular disease, and cerebrovascular disease. These problems can result in organ and tissue damage in approximately one-third to one-half of patients diagnosed with diabetes [10]. Diabetic retinopathy is the most prevalent microvascular condition, significantly contributing to global blindness rates [11]. The current study observed a male predominance, with 72% of participants being male. A separate study was undertaken by Niveditha H [12] including 50 individuals, comprising 31 males and 19 females. Singh et al. [13] observed in their study that 57.8% of participants were male and 42.1% were female. Kumar et al. [14] found that 55% of the participants were male and 45% were female. Santos et al. [15] similarly reported findings in their investigation. A 2016 study on the Indian population revealed that the prevalence of diabetic retinopathy was markedly greater in men (68.5%) than in women, and it was most prevalent among those aged 50 to 70 years (75.5%) [16]. A separate study conducted by Manaviat et al. [17] included a predominance of female participants (58.64%), and the average age of the subjects was similar to that in our current study (52.23±11.34 years). In contrast, the research conducted by He et al. [18] had predominantly male patients (57%) with an average age of 59.69±12.28 years. The data indicate that the gender distribution of individuals with diabetes and microalbuminuria may differ and is specific to each research, rather than representative of the total community.

The largest proportion of participants in the current study was aged between 40.1 and 50 years, accounting for 30% of the total. The mean age of the participants was calculated to be 52.23 ± 11.34 years. This study focused on patients with type II diabetes mellitus, a condition that is more prevalent in older adults compared to younger individuals. Kumar et al. [14] made similar observations, noting that the majority of participants in their study were aged 50-60 years, followed by those aged 40-49 years. Similarly, Eqbal et al. [19] reported that the predominant age group in their study was 51-60 years, followed by the 41-50 year age group. Additionally, in a study with 232 individuals suffering from diabetic retinopathy, Singh et al. [13] found that most participants (69.1%) were aged between 51 and 65 years.

In the present study, the majority of individuals had a diabetes mellitus (DM) history of 10.1 to 20 years (35%), followed by 34% with over 20 years of DM history, and 31% with a duration of 1 to 10 years. An extended duration of diabetes correlated positively with the severity of diabetic retinopathy, with the highest prevalence of proliferative diabetic retinopathy noted in individuals with diabetes lasting over 20 years. Prolonged hyperglycemia elevates the risk of microvascular problems, such as diabetic retinopathy (DR). Niveditha et al. [12] reported a mean duration of diabetes mellitus of 6.9 years. In the CURES Eye research, 41.8% of participants exhibited diabetic retinopathy (DR) after 15 years of diabetes, with the severity of DR escalating in direct correlation to the length of diabetes [20]. Furthermore, studies indicate that the risk of diabetic retinopathy (DR) escalates by 1.89 times for each subsequent five-year period of diabetes duration. An increased prevalence of diabetic retinopathy (DR) was associated with an extended period of diabetes, a conclusion previously reached by the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) [21]. Consequently, early screening and regular follow-up for individuals with prolonged diabetes durations are essential for the detection and management of diabetic retinopathy in its initial phases.

Poor glycemic control, indicated by greater HbA1c levels (>9%), was correlated with a higher prevalence of PDR, although this association did not achieve statistical significance in our sample. This aligns with the findings of the prior study conducted by Almutairi et al [22]. Numerous studies demonstrated a substantial correlation between HbA1c levels and the severity of diabetic retinopathy (DR) [22]. Extended hyperglycemia results in microvascular injury, facilitating the advancement of diabetic retinopathy [23, 24]. The analysis of the relationship between the length of diabetes mellitus (DM) and HbA1c levels revealed that patients with a prolonged period of DM while achieving good to fair glycemic control, had a higher incidence of severe diabetic retinopathy compared to those with a shorter duration of DM under similar glycemic conditions.

The study showed a statistically significant correlation between the utilization of anti-diabetic drugs and the severity of diabetic retinopathy. Individuals utilizing insulin, whether solely or in conjunction with oral hypoglycaemic medications, demonstrated elevated incidences of moderate-to-severe diabetic retinopathy relative to those using only oral medicines. This observation may indicate that insulin utilization is more prevalent among patients with chronic or inadequately managed diabetes, factors intrinsically linked to heightened diabetic retinopathy severity [25, 26]. It emphasizes the necessity of integrated management solutions that merge pharmaceutical treatments with lifestyle changes to enhance results. Macular edema had a notable correlation with severe non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). This corresponds with previous studies that recognized macular edema as a significant factor influencing visual impairment and severe stages of diabetic retinopathy [27-29]. Unexpectedly, neuropathy and nephropathy exhibited no significant correlation with the severity of diabetic retinopathy in this investigation, potentially attributable to the limited number of patients experiencing these problems. However, the interaction among these problems necessitates additional investigation, as prior research has confirmed their coexistence with diabetic retinopathy in inadequately managed diabetes [30, 31]. This study's findings underscore the necessity for early screening and prompt care of diabetic retinopathy, especially in individuals with inadequate glycaemic control, prolonged diabetes, and those undergoing insulin treatment. Routine fundus examinations and specific therapies to regulate glucose levels, blood pressure, and lipid profiles are crucial for averting the advancement to severe stages of diabetic retinopathy. Furthermore, treating retinal edema with suitable therapy, such as intravitreal anti-vascular endothelial growth factor (VEGF) injections, may alleviate the impact of vision-threatening diabetic retinopathy (DR) [32].

This study highlights the critical role of early identification and management of key risk factors, such as glycaemic control and diabetes duration, in determining the severity of diabetic retinopathy. Implementing comprehensive diabetes care strategies, including patient education, strict glycaemic monitoring, and routine ophthalmologic evaluations, is essential in reducing the burden of diabetic retinopathy and preserving visual function. Enhancing awareness among patients and healthcare providers can facilitate early intervention and improve long-term outcomes. Future research should focus on evaluating targeted interventions that can effectively slow disease progression across diverse patient populations and clinical settings.

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