Association of systemic risk factors with the severity of retinal hard exudates in a north Indian population with type 2 diabetesN Sachdev1, A Sahni2
1 Department of Ophthalmology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Ophthalmology, Govt. Medical College and Hospital, Chandigarh, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.62419
Source of Support: None, Conflict of Interest: None
Background: The various risk factors for diabetic retinopathy and its spectrum are still poorly understood in the Indian population. Aims: To study the association of various systemic risk factors with retinal hard exudates in type 2 diabetic north Indian patients and to measure the incidence of dyslipidemia in them. Settings and Design: A tertiary-hospital-based cross-sectional study. Materials and Methods: An observational case-study which included 180 type 2 diabetic patients (180 eyes) of nonproliferative diabetic retinopathy (NPDR) with clinically significant macular edema (CSME). In these patients the retinal hard exudates were graded on a central 500 fundus picture using modified Airlie House classification and divided into three groups of absent or minimal hard exudates (Group 1), hard exudates present (Group 2) and prominent hard exudates (Group 3). Their association with various risk factors, namely the age of onset of diabetes and its duration, gender, insulin therapy, and various systemic parameters like hypertension, blood hemoglobin, glycosylated hemoglobin, serum (s.) creatinine levels, 24-h proteinuria and complete lipid profile including total s. cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), very low-density lipoprotein cholesterol (VLDL) and s. triglyceride (TG) was studied. The incidence of dyslipidemia was also calculated among these groups of patients. Statistical Analysis: ANOVA test, linear regression analysis and Spearman's correlation test. Results: On univariate analysis, the retinal hard exudates were significantly associated with s. creatinine (P=0.016), systolic blood pressure (P=0.014), s. cholesterol (P<0.001), s. LDL (P=0.008) and s. TG (P=0.013) levels. While on linear regression analysis, s. cholesterol (P<0.001) and s. LDL cholesterol (P=0.028) were found to be independent risk factors affecting the density of retinal hard exudates. On Spearman's correlation test, the retinal hard exudates showed a significant positive correlation with systolic blood pressure (P=0.019), s. cholesterol (P<0.001), LDL (P=0.002) and TG (P=0.014) levels. The incidence of dyslipidemia varied from as high as nearly 70% among patients of Group 3 compared to as low as 18% among Group 1 patients. Conclusion: Serum cholesterol and LDL are independent risk factors for retinal hard exudates in type 2 diabetic north Indian patients who suffer from a remarkably high incidence of dyslipidemia.
Keywords: Diabetic retinopathy, hard exudates, lipid profile
Clinically significant macular edema (CSME) is the most common cause of moderate visual loss in nonproliferative diabetic retinopathy (NPDR).  CSME is defined as retinal thickening at or within 500 microns from the centre of macula, hard exudates at or within 500 microns from the centre of macula, if there is thickening of the adjacent retina or presence of an area or areas of retinal thickening at least 1 disc area in size, at least a part of which is within 1 disc diameter of the centre of the macula. , Hence, retinal hard exudates are one of a constellation of retinal lesions that characterize diabetic retinopathy and CSME. 
Various previous studies on retinal hard exudates and their risk factors have been conducted on Caucasian and black American populations. ,,,,, However, recent studies have suggested that Indians, especially the north Indian population, is more predisposed to develop diabetes and its related complications. ,,,,, Hence, we conducted a study to determine the association between various systemic risk factors and severity of retinal hard exudates among type 2 diabetic north Indian patients. We also studied the incidence of dyslipidemia in these patients.
This observational tertiary-hospital-based cross-sectional case-study enrolled 180 consecutive patients with type 2 diabetes mellitus having CSME and NPDR in at least one eye attending the Retina Clinic of our institute. The study was approved by the ethical review board of the institute and a written informed consent was obtained from all the participating patients. All the subjects underwent a detailed ocular examination, including recording of best-corrected visual acuity and a dilated fundus examination. Single eye was enrolled for each patient and in patients in whom both the eyes fulfilled the inclusion criteria, the eye with the poorer vision was assigned to the patient. However, eyes with significant media haze preventing adequate visualization of the fundus to permit grading of hard exudates were excluded from the study.
The grading of retinal hard exudates was performed by utilizing the modified Airlie House Classification on a central 50° digital fundus photograph.  The modified Airlie House Classification used is as follows: Grade 0 - No evidence of hard exudates; Grade 1 - Questionable hard exudates present; Grade 2 - Hard exudates less than standard photograph 3; Grade 3 - Hard exudates greater than or equal to standard photograph 3, but less than standard photograph 5; Grade 4 - Hard exudates greater than or equal to standard photograph 5, but less than standard photograph 4 and Grade 5 - Hard exudates greater than or equal to standard photograph 4. These grades were further divided into three groups of patient severity as follows: Group 1 (absent or minimal hard exudates) included patients with Grade 0, 1 or 2 hard exudates; Group 2 (hard exudates present) included patients with Grade 3 or 4 hard exudates and Group 3 (prominent hard exudates) included patients with Grade 5 hard exudates.
Details regarding various systemic risk factors, namely the age of onset of diabetes, disease duration and treatment history were obtained. The measurement of other systemic parameters like systolic and diastolic blood pressure, blood hemoglobin, glycosylated hemoglobin, serum creatinine, 24-h proteinuria and complete lipid profile including total serum (s.) cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), very low-density lipoprotein cholesterol (VLDL) and s. Triglyceride (TG) was performed. The association of above risk factors with the severity of retinal hard exudates was studied using univariate analysis on one-way ANOVA test. The above factors which returned a result of P<0.1 on ANOVA test were further evaluated for their independent association with retinal hard exudates using multiple linear regression analysis. Similarly, Spearman's correlation test was performed to study the correlation between the above risk factors and the severity of retinal hard exudates. Statistically significant levels were assumed at a P value of less than 0.05. We also measured the incidence of dyslipidemia in this group of patients by comparing their s. cholesterol and LDL levels with our laboratory standards for diabetic patients where s.LDL levels >130 mg/dl and s. cholesterol >200 mg/dl are assumed as abnormal.
The study included 180 patients (180 eyes) with nonproliferative diabetic retinopathy (NPDR) and clinically significant macular edema (CSME). There were 116 male patients and 64 female patients. The mean (± standard deviation) age was 55.6 ± 7.4 years. One hundred and twenty-five patients (69.4%) were receiving oral hypoglycemic agents, 50 patients (27.8%) were on insulin therapy and five patients (2.8%) were on dietary control. One hundred and eighteen patients (65.5%) had associated history of hypertension and were under treatment. The mean best-corrected visual acuity in these patients at the time of enrollment was 0.56 units on LogMar scale (range 0.0 to 1.5). On Chi-square test, sex of the patient (P=0.305) and their treatment modality (P=0.166) did not exhibit any significant association with the density of retinal hard exudates.
Thirty-three eyes had hard exudates of Grade 2 or less and were included in Group 1 (absent or minimal hard exudates). Similarly, hard exudates of Grade 3 or 4 were seen in 90 eyes who were included in Group 2 (hard exudates present) while the remaining 57 eyes had Grade 5 hard exudates and were included in Group 3 (prominent hard exudates). The distribution of various parameters among the three groups is provided in [Table 1]. On univariate analysis by one-way ANOVA test, the retinal hard exudates were found to be significantly associated with s. creatinine (P=0.016), systolic blood pressure (P=0.014), s. cholesterol (P<0.001), s. LDL (P=0.008) and s. TG (P=0.013) levels. While on linear regression analysis, s. cholesterol (P<0.001) and s. LDL (P=0.028) were found to be the independent risk factors affecting the severity of retinal hard exudates. On Spearman's correlation test, the retinal hard exudates showed a significant positive correlation with systolic blood pressure (P=0.019), s. cholesterol (P<0.001), s. LDL (P=0.002) and TG (P=0.014) levels.
Among Group 1 patients, six patients (18.2%) had elevated s. LDL levels (>130 mg/dl) while seven patients (21.2%) had elevated s. cholesterol (>200 mg/dl) levels. Among Group 2 patients, 41 patients (45.5%) had elevated s. LDL while 46 patients (51.1%) had elevated s. cholesterol levels. The corresponding figures for Group 3 were 33 patients (57.9%) and 40 patients (70.2%) respectively.
Retinal hard exudates usually encountered in patients with diabetic retinopathy result from the leakage of lipoproteins from retinal capillaries into the extracellular space of the retina. As the density of these hard exudates increases, they tend to migrate towards the foveal centre where their deposition predisposes to development of subfoveal fibrosis leading to irreversible visual loss. In fact early treatment diabetic retinopathy study has demonstrated an independent adverse effect of these retinal hard exudates on the visual acuity of the patients. ,
Previous studies conducted predominantly in the Caucasian white population have shown significant association between retinal hard exudates and the s. cholesterol and LDL levels. , Roy and Klein have documented that the presence of proteinuria, male sex, higher LDL-cholesterol levels and longer duration of diabetes are significantly and independently associated with the severity of retinal hard exudates in the African American diabetic population. 6 Subsequently, Miljanovic et al., in a prospective study demonstrated that elevated serum lipids, particularly total-to-HDL cholesterol ratio and triglycerides, are independent risk factors for both CSME and retinal hard exudates. 
Type 2 diabetes mellitus (DM) has emerged as a major global public health problem. This is more so in developing countries like India which is expected to bear the brunt of this disease and emerge as the world capital of diabetes mellitus by 2030.  In the Indian population, the prevalence of type 2 DM ranges from 2.7% in rural India to nearly 14% in urban India. Previous studies in the north Indian population have documented that they are at a high risk of developing diabetes and its related complications in comparison with other Asian communities. ,,,,, A higher prevalence is, in part, attributed to the genetic predisposition of the individual and to a host of various morphological/biological parameters more commonly seen in our north Indian population like physical inactivity, upper-body adiposity, higher body fat percent, dyslipidemia and exaggerated insulin resistance.
Pradeepa et al., in a study from urban south India, identified higher HbA1c levels, male gender, longer duration of diabetes, macroalbuminuria and insulin therapy as independent risk factors for diabetic retinopathy.  Similarly Rani et al., in a mass screening study from southern rural districts of Tamil Nadu identified longer duration of diabetes, lean body mass index (lower BMI), higher systolic blood pressure and insulin treatment as the systemic risk factors significantly associated with referable diabetic retinopathy.  However, the above studies did not look into their lipid levels.
The present study suggests that serum cholesterol and LDL levels have a significant and independent effect on the severity of retinal hard exudates. We also observed an increasing incidence of dyslipidemia with progressive grades of hard exudates in this subgroup of diabetic patients with CSME. The limitation of the present study is that since it is based in a tertiary level referral hospital, a majority of the cases are complex and systemically uncontrolled, and hence it may account for the relatively high incidence of dyslipidemia observed. Moreover, the association of BMI of these patients with the observed dyslipidemia and the severity of retinal hard exudates needs to be further evaluated.
The present study suggests that the treating ophthalmologists should get a complete blood lipid profile test done if the patient has significant retinal hard exudates on fundus examination. This study also highlights the need for routine prescription of lipid-lowering drugs in addition to dietary restrictions and regular physical exercise in north Indian diabetic patients with documented retinal hard exudates due to the widespread occurrence of dyslipidemia in these patients. These drugs have already proven beneficial effect in reducing the risk of adverse cardiovascular events like myocardial infarction and stroke. ,
Prof Amod Gupta, Prof and Head, Dept of Ophthalmology, PGIMER. Dr. Vishali Gupta, Associate Prof, Dept of Ophthalmology, PGIMER.