Risk factors of focal maculopathy in patients with Type 2 diabetes mellitus with hard exudates: A hospital-based case–control study Patra R, Bhat VG, Goru KB, Rao N L,

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Risk factors of focal maculopathy in patients with Type 2 diabetes mellitus with hard exudates: A hospital-based case–control study

Rajkumar Patra¹, Vinayak Ganesh Bhat², Krishna Babu Goru³, N Lakshmana Rao³
¹ Department of Ophthalmology, Maharajah's Institute of Medical Sciences, Vizianagaram, Andhra Pradesh, India
² Department of Biochemistry, Maharajah's Institute of Medical Sciences, Vizianagaram, Andhra Pradesh, India
³ Department of Community Medicine, Maharajah's Institute of Medical Sciences, Vizianagaram, Andhra Pradesh, India

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Date of Submission	26-Oct-2022
Date of Decision	23-Dec-2022
Date of Acceptance	26-Dec-2022
Date of Web Publication	09-May-2023

Abstract

Background: Dyslipidemia and hard exudates of the retina have an intricate association. Increased lipid levels cause increased hard exudates. Many studies found dyslipidemia as an independent risk factor for the development of hard exudates in maculopathy.
Objectives: The objective of this study was the association between dyslipidemia and the presence of hard exudates among focal maculopathy patients with and without hard exudates.
Materials and Methods: This was a hospital-based case–control study. This study included 60 patients with focal maculopathy in type 2 diabetes mellitus (DM) with hard exudates. Sixty patients with Focal maculopathy in type 2 DM without hard exudates were taken as control.
Results: Dyslipidemia was significantly seen (P < 0.05) in cases compared to participants. Total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and very LDL-C were significantly higher in cases compared to controls. High-density lipoprotein cholesterol (HDL-C) had the opposite outcome. HDL-C was significantly lower in cases compared to controls.
Conclusion: Dyslipidemia was a strong risk factor for the formation of hard exudates in the macula. An increase in lipid levels increased the hard exudates concentration in the macula and retina.

Keywords: Dyslipidemia, focal diabetic maculopathy, hard exudates, lipid levels, macula, type 2 diabetes mellitus

How to cite this URL:
Patra R, Bhat VG, Goru KB, Rao N L. Risk factors of focal maculopathy in patients with Type 2 diabetes mellitus with hard exudates: A hospital-based case–control study. MRIMS J Health Sci [Epub ahead of print] [cited 2023 May 29]. Available from: http://www.mrimsjournal.com/preprintarticle.asp?id=376061

Introduction

Diabetes mellitus (DM) has an immense burden on the Indian population. The type 2 DM prevalence in India was found to be 9.3% in 2022.^[1] The prevalence of impaired fasting blood glucose was found to be 24.5%.^[1] Diabetic maculopathy is a condition where the macula is affected due to DM. Many studies found dyslipidemia as an independent risk factor for diabetic macular edema (DME) and vision loss. Increased levels of serum cholesterol and triglycerides (TG) are associated with higher severity of hard exudates.^[2],[3]

DM is a chronic metabolic disorder. It is caused by an absolute or relative deficiency of the hormone insulin. Diabetic maculopathy is a condition where the macula is affected due to DM. As the macula is an important part of the retina, vision gets severely impaired in patients with diabetic retinopathy. Wisconsin Epidemiological Study for Diabetic Retinopathy (WESDR) study^[4] determined a 10-year date of developing DME among 25.4% of older onset diabetes patients taking insulin and 13.9% of patients not taking insulin. DCCT study found 27% of patients having macular edema in 9 years. It was found that diabetes duration was an independent risk factor for retinopathy^[5],[6] and maculopathy development. Many studies found dyslipidemia as another independent risk factor for the loss of vision and DME. Elevated serum cholesterol levels are associated with increased severity of hard exudates.^[7],[8],[9] Hard exudates are intraretinal lipid deposits formed due to the leakage of lipids and proteins from retinal capillaries.

Diabetes maculopathy has more impact on the vision of the patient than overall retinopathy. Retinal hard exudates are formed in diabetic maculopathy due to the lipoprotein's leakage from the capillaries of the retina into the retinal extracellular space. These hard exudates slowly start migrating toward the foveal center due to increased density and concentration over time.^[10] Early diagnosis of dyslipidemia in cases of type 2 DM, can drastically decrease hard exudates in the retina and prevent irreversible blindness caused by hard exudates.

This study aimed to study the association of various lipid profile components total cholesterol (TC), TG, low-density lipoprotein cholesterol (LDL-C), very LDL-C (VLDL-C), and high-density lipoprotein cholesterol (HDL-C) in the formation of hard exudates in patients with focal maculopathy in type 2 DM. The objective was to understand dyslipidemia as a risk factor for the development of hard exudates.

Materials and Methods

This was a hospital-based case–control study. This study included 60 patients with focal maculopathy in type 2 DM with hard exudates (Group A). Sixty patients with focal maculopathy in type 2 DM without hard exudates (Group B) were taken as control. Age and gender were matched among both groups. These were the patients who attended the ophthalmology outpatient department of the institution for 1.5 years from January 15, 2021, to July 15, 2022. Convenience sampling was done over 1.5 years. All patients who visited the institution during the period with our criteria were enrolled in the study. The protocol of this study was approved by the institution's ethical committee with Lr No. IEC/107/21. Written informed consent was taken from all study participants.

Inclusion criteria involved confirmed patients of type 2 DM with focal maculopathy. Only cases with a duration between 10 and 15 years were taken into the study. Participants were matched with cases for better accuracy. Both group participants were on hypoglycemic drugs insulin or both. They were not on any hypolipidemic drugs or pioglitazone.

Exclusion criteria included DM duration of fewer than 10 years and more than 15 years, other types of maculopathy (diffuse and ischemic), patients on hypolipidemic drugs, pioglitazone (hypoglycemic drugs), high myopia, retinitis pigmentosa, patients with retinopathy without maculopathy, central retinal vein occlusion, hypertensive retinopathy (III and IV), acute or chronic illness, liver or renal disorders, and other systemic diseases were also excluded from the study.

Detailed clinical history was taken from all participants who participated in the study. Details including age, sex, blood glucose, and associated systemic complications such as neuropathy, nephropathy, hypertension, and hyperlipidemia were noted. History relevant to the study, the onset of diabetes, duration of illness, family history, drug schedule, and dietary habits were taken. Complete ocular examination was done in the department of ophthalmology, including best-corrected visual acuity of the participant, intraocular pressure, anterior segment examination using slip-lamp biomicroscope with lens type 90D, detailed fundus examination using indirect ophthalmoscope with 20D lens, and fundus photography with Zeiss FF450 plus fundus camera.

After obtaining informed consent from the participant, 5 mL of the venous blood sample was collected from all participants under aseptic conditions. After adequate clotting, the serum tube was centrifuged. The serum supernatant from the test tube was aliquoted. The same-day serum was tested for fasting blood sugar (FBS) (GOD-POD method), HbA1c (cation exchange resin method), TC (CHOD-PAP method), TG (GPO-PAP method), LDL-C (Friedewald's formula), VLDL-C (Friedewald's equation), HDL-C (direct endpoint enzymatic method).

Data were statistically analyzed using IBM SPSS Statistics Version 21.0' Statistical software and Microsoft Excel 2007. Quantitative variables were expressed in mean and standard deviations (SDs). The student unpaired test was used for a two-group mean comparison. For all statistical analyses, P < 0.05 was considered statistically significant.

Results

As shown in [Table 1], a total of 60 participants of diabetic focal maculopathy with hard exudates (Group A, cases) were selected for the study among which 25 participants (41.7%) were female and 35 participants (58.3%) were male. Similarly, 60 participants of diabetic focal maculopathy without hard exudates (Group B, control) were studied. Thirty-two participants (53.3%) were female and 28 (46.7%) participants were male in the control group. And as per [Table 2], the mean age with SD of Group A was 38.84 ± 15.7 years and of Group B was 39.40 ± 16.2 years. P value was found to be 0.85 and not statistically significant. Group A's mean FBS was 179.86 ± 28.7 mg/dl, and Group B's was 192.83 ± 24.1 mg/dl. P value in FBS values was found to be 0.01 (<0.05). Group A had HbA1c 9.8% ± 1.3% and Group B had 8.75% ± 1.1%. HbA1c also noted a P value of 0.00. Groups A and B had a significant association among FBS and HbA1C values.

Table 1: Distribution of participants based on age and gender

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Table 2: Mean, standard deviation, and P value of age, fasting blood sugar, and glycated hemoglobin

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[Table 3] showed various lipid profiles in two study groups. Group A's mean ± SD TC was 280.84 ± 18.8 mg/dl, and Group B was 184.12 ± 11.9 mg/dl. A P value of 0.00 (<0.05) was noted in both groups. Group A's mean ± SD TG was 219.27 ± 27.4 mg/dl, and Group B was 164.8 ± 11.7 mg/dl. A P value of 0.00 (<0.05) was noted in both groups. Group A's mean ± SD LDL-C was 193.38 ± 16.4 mg/dl, and Group B was 126.27 ± 20.7 mg/dl. The P value was found to be 0.00 (<0.05) in both groups. Group A's mean ± SD HDL-C was 24.98 ± 4.9 mg/dl, and Group B was 34.92 ± 4.8 mg/dl. The P value was found to be 0.00 (<0.05). Group A's mean ± SD VLDL-C was 44.55 ± 5.1 mg/dl, and Group B was 33.73 ± 6.2 mg/dl. A P value of 0.00 (<0.05) was seen even in this parameter. A strong association was found in all five parameters of the lipid profile. Total Cholesterol (TC), Triglycerides (TG), Low-Density Lipoprotein – Cholesterol (LDL-C) and Very Low-Density Lipoprotein – Cholesterol (VLDL-C) ) were found to be significantly (P < 0.05) higher in Group A (cases) compared to Group B (control). High-Density Lipoprotein – Cholesterol (HDL-C) had the opposite outcome. High-Density Lipoprotein – Cholesterol (HDL-C) was found to be significantly (P < 0.05) lower in Group A (cases) compared to Group B (control).

Table 3: Mean, standard deviation, and P value of total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol

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Discussion

Focal maculopathy is the most common type of maculopathy in type 2 DM. It is also the most common reason among maculopathy for vision loss, as it affects the central macula. Hard exudates are intraretinal lipid deposits of whitish-yellow color. They are formed due to the leakage of lipids and proteins from retinal capillaries. It was found that the severity of hard exudates increases in dyslipidemia. Many studies have proved, elevated serum cholesterol levels are associated with increased severity of hard exudates.^[7],[8],[9] As dyslipidemia has more concentration of serum cholesterol, TG, and other lipid molecules than desired, excess cholesterol tends to leak into retinal capillaries along with proteins. On a prolonged period, this accumulation increases exponentially compared to a person without dyslipidemia. This makes dyslipidemia, a risk factor for increased hard exudates in cases of dyslipidemia.^[6] There are many other contributing factors to the formation of hard exudates. Type 2 DM is a multisystem disorder that affects all metabolisms. Due to insulin resistance, the liver gets filled with increased concentrations of glucose and fatty acids. Clearance of TG and LDL-C are decreased in the liver due to increased apolipoprotein B production and less activity of lipoprotein lipase.^[6] Increased TG raises the viscosity of blood and alter fibrinolytic activity. This causes the formation of hard exudates. TGs also alter the permeability of cell membranes causing hemorrhage and edema. The local inflammatory response is set in which causes the release of cytokines and growth factors. This causes the neovascularization of the retina.^[10],[11] So multifactorial pathophysiology sets in causing excess hard exudates in dyslipidemia participants compared to participants without dyslipidemia. Animal studies had also shown retinal vasculature endothelial dysfunction caused blood–brain barrier breakdown.^{[11],[12],[13]} This association was also confirmed by a study^[14] which proved decreased production of hard exudates with lipid-lowering drugs.

The present case–control study showed a statistically significant (P = 0.00) increase in TC, TG, LDL-C, and VLDL-C between Group A and Group B and a statistically significant decrease in HDL-C levels between the two groups. A strong association (P = 0.00) was found in all five lipid profile parameters. The current study is one of a kind. This study tried to understand the correlation between lipid profiles in a closed group of focal diabetic maculopathy with and without hard exudates. Many studies had been done in India and abroad to understand the correlation between maculopathy and retinopathy.

Klein et al.^[15] in WESDR, correlated raised serum cholesterol levels with hard exudates in the macula. It was a 25-year extensive cohort study with 1370 study participants. Early treatment diabetic retinopathy study (ETDRS) by Chew et al.^[3] found an association between LDL-C and TC with hard exudates onset and severity in the retina. Diabetes control and complications trial (DCCT) Cohort study by Lyons et al.^[16] found a positive association with TG and a negative association between HDL-C with the production of hard exudates. The Chennai Urban Rural Epidemiology Study (CURES) eye study done in Chennai by Rema et al.^[17] found an association between TG and LDL-C with DME. Sachdev and Sahni^[18] found that increased TC and LDL-C were risk factors for retinal hard exudates in north Indian type 2 DM patients. Keech et al.^[14] showed that lipid-lowering drugs decrease the progression of diabetic retinopathy and hard exudate formation. These findings were considered important because maculopathy is a part of total retinopathy. A study on diabetic maculopathy by Zander et al.^[19] also showed a significant positive correlation between TC and TG in type 1 and type 2 DM participants. Our findings correlated with multiple studies done in India and abroad.

Potential bias was limited in the study. Patients were picked up based on the disease criteria. The primary researchers were a trained ophthalmologist and a trained biochemist. No other ophthalmologist or biochemist was involved in the study. The generalizability of the study was limited as the study had been done in a hospital setting. If applicable, the generalizability of the study was limited to Vizianagaram town of Andhra Pradesh. This study recommends ophthalmologists check fasting lipid profiles in diabetic maculopathy cases with hard exudates. The use of lipid-lowering drugs in the early treatment of diabetic maculopathy may benefit patients with better visual acuity.

Conclusion

Dyslipidemia is an independent risk factor for the development of hard exudates in cases of focal maculopathy. Periodic checking of the lipid profile in all type 2 DM patients with a duration of diabetes >5 years is essential. This reduces possible irreversible blindness caused by hard exudates in the macula and other parts of the retina.

Limitations

This study was done on patients visiting the institution. The sample size was limited to 60 in both case and control groups. Hence, the exact status can be explained with sampling done in both rural and urban communities. To avoid any possible bias, a large-scale population can be taken to understand the association.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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