Serum lipid profile in diabetic macular edema

Journal of Diabetes and Its Complications 23 (2009) 244 – 248 WWW.JDCJOURNAL.COM Serum lipid profile in diabetic macular edema Pinar Altiaylik Ozer⁎, Nurten Unlu, Muhammed Necati Demir, Dicle Oncel Hazirolan, Mehmet Akif Acar, Sunay Duman Ophthalmology Department, Ankara Education and Research Hospital, Ankara, Turkey Received 30 August 2007; received in revised form 17 November 2007; accepted 7 December 2007 Abstract Purpose: To evaluate the correlation of lipid profile and clinical presentation of macular edema in Type 2 diabetes mellitus (DM) patients. Materials and Methods: The study included 20 patients with chronic diabetic macular edema and plaque-like hard exudates (Group 1), 20 patients with diabetic macular edema (Group 2), and 20 DM patients but without retinopathy (Group 3). Diabetic retinopathy was classified according to the Early Treatment Diabetic Retinopathy Study grading system. Sample t test was used to evaluate the association between the fasting serum lipid [total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL)], glycosylated hemoglobin (HbA1c), fasting blood glucose, creatinine levels, and the clinical findings. P values b.05 were considered statistically significant. Results: There was no difference between fasting serum lipids and HbA1c levels. Duration of diabetes was shorter in Group 3 than in Groups 1 and 2. Patients in Group 1 had longer duration of diabetes than others (Pb.05). Creatinine levels in Group 1 were higher than in other groups (Pb.05). Although there was no correlation between fasting blood glucose and HbA1c levels, HbA1c was higher in all three groups from the baseline-normal limits (Pb.05). Conclusion: No correlation was found between serum lipid levels and macular edema severity, but the duration of diabetes was demonstrated as a significant factor in the progression of macular edema. High HbA1c levels in all patients highlight the importance of intense glycemic control in diabetic patients. © 2009 Elsevier Inc. All rights reserved. Keywords: Diabetic macular edema; HbA1c; Total cholesterol; Triglyceride; LDL; HDL 1. Introduction Previous studies have shown that the risk factors for diabetic retinopathy (DR) are the degree of glycemic and blood pressure control, duration of diabetes, presence of nephropathy, and raised serum lipids (Aiello & Cahilli, 2001; Porta & Bandello, 2002). The association between serum lipids and DR has been widely studied but has produced ⁎ Corresponding author. Tel.: +90 312 2870376/+90 505 670 56 47; fax: +90 312 5620808. E-mail addresses: [email protected] (P.A. Ozer), [email protected] (N. Unlu), [email protected] (M.N. Demir), [email protected] (D.O. Hazirolan), [email protected] (M.A. Acar), [email protected] (S. Duman). 1056-8727/07/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jdiacomp.2007.12.004 conflicting results due to differences in the methodology and ethnicity (Avci & Kaderli, 2006; Chew & Klein, 1996; Dornan, Carter, Bron, Turner, & Mann, 1982; Early Treatment of Diabetic Retinopathy Study Research Group, 1985; Early Treatment of Diabetic Retinopathy Study Research Group, 1991; El Haddad & Saad, 1998; Ferris & Chew, 1996; Klein & Klein, 1984; Klein & Klein, 1999; Kordonouri & Danne, 1996; Marshall & Garg, 1993; Mouton & Gill, 1988; Rema & Mohan, 1984; Sinav & Onelge, n.d; Weber & Burger, 1986). Macular edema is the most important cause of deterioration of vision in patients with DR. Approximately 29% of all patients with diabetes of more than 20 years duration are at risk of macular edema (Klein & Klein, 1984). Macular edema can be subdivided into focal and diffuse types, and in severe cases, the central vision of patients declines because 245 P.A. Ozer et al. / Journal of Diabetes and Its Complications 23 (2009) 244–248 Table 1 The demographic characteristics of the patients and severity of retinopathies Range of age (years) Group 1 (n=20) Group 2 (n=20) Group 3 (n=20) 57–85 52–82 40–71 Gender Female (%) Male (%) Mean duration of diabetes (years) 55 (n=11) 50 (n=10) 60 (n=12) 45 (n=9) 50 (n=10) 40 (n=8) 14±12 10±7 5±4 Mean time of follow-up (months) Hypertension (%) 18±5 7±4 60 (n=12) 55 (n=11) 75 (n=15) Severity of retinopathy NPDR (%) PDR (%) 50 (n=10) 75 (n=15) 50 (n=10) 25 (n=5) Group 1, chronic diabetic macular edema with plaque-like hard exudates; Group 2, DR with macular edema; Group 3, non-DR. of confluent hard exudates in the macular region. In these cases, the visual loss is usually severe and irreversible (Avci & Kaderli, 2006). Pathogenesis underlying the diabetic microvascular pathologies seem to be similar. Changes in the extracellular matrix, increased thickness of basement membranes, and loss of pericytes are the common, early events of DR and diabetic nephropathy (Camera & Hopps, 2007). In addition to the mechanisms underlying the pathogenesis of retinopathy, elevated lipid concentrations may be correlated to an increase in diabetic macular edema, by way of increased deposition of hard exudates in the retina. Rema and Mohan (1984) showed a relationship between increased serum lowdensity lipoprotein (LDL) cholesterol levels and severity of diabetic maculopathy. This study aims to provide a contribution to the literature, in terms of determining the effect of serum lipids on diabetic macular edema, which is one of the most common results of endothelial dysfunction in retinal vasculature. We also examined the correlation of serum creatinine levels with the severity of macular edema, which is supposed to reflect the dysfunction in renal vasculature that may accompany the dysfunction in retinal vasculature. 2. Materials and methods Data from 20 Type 2 diabetes mellitus (DM) patients with chronic diabetic macular edema and plaque-like hard exudates (hard exudates larger or equal to a half optic disc diameter) (Group 1), 20 Type 2 DM patients with macular edema in association to DR (Group 2), and 20 patients with Type 2 DM but without any retinopathy (Group 3) were included in the study. Patients with Type 1 DM, chronic renal failure, uncontrolled hypertension with antihypertensive medications, and patients with a history of any intraocular surgery were excluded. Time of follow-up was retrospectively examined for patients in Groups 1 and 2 since these patients were in regular follow-up by our retina department. Patients in Group 3 were randomly selected from our outpatient department, included in the study as a control group and cross-sectionally analyzed. Age, gender, duration of diabetes, and type of the current treatment (with oral antidiabetics or insulin) were determined; and fundus examinations with 90D lenses in each visit and four field retinal color photography were retrospectively examined for each patient. Optic coherence tomography (OCT) was applied to all patients with macular edema, and fundus flourescein angiography (FFA) was carried on patients in whom the necessity of additional treatment was needed. Fundus examinations were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system (Early Treatment of Diabetic Retinopathy Study Research Group, 1991). Fundus photographs were assessed in comparison with the ETDRS standard photographs for severity of retinopathy (Early Treatment of Diabetic Retinopathy Study Research Group, 1991) The minimum criterion for the diagnosis of DR was the presence of at least one definite microaneurysm in any field of the eye. Photographs were assessed and assigned a retinopathy level, and the final diagnosis for each patient was determined from the grading of the worst eye using ETDRS final retinopathy scale for individual eyes. Briefly, Level 10 represents no retinopathy (no DR); Level 20, Level 53, nonproliferative retinopathy (NPDR); and Level ≥61, proliferative DR (PDR). Diabetic macular edema was defined as retinal thickening at or within one disc diameter of the center of macula or the presence of definite hard exudates (Early Treatment of Diabetic Retinopathy Study Research Group, 1985). Fasting serum lipid levels, fasting blood glucose, creatinine, and glycosylated hemoglobin (HbA1c) levels of patients were detected simultaneously at the same visit of each patient. Records of the subjects were retrospectively searched for these biochemical parameters checked out in each visit. But due to the deficient recordings of some visits, instead of taking an average, values of the last visit were taken. The association between the fasting serum lipid levels [total cholesterol, triglyceride, LDL, high-density lipoprotein (HDL)], HbA1c, fasting blood glucose, creatinine levels, and macular edema status were investigated. 2.1. Statistical analysis Analysis was performed with SPSS (SPSS for Windows, version 10.0, SPSS, Chicago, IL) software. One-way ANOVA (with post hoc Tukey analysis) or Student's t test, as appropriate, was used to compare groups for continuous variables. Logistic regression was used to calculate the association between fasting serum lipid levels 246 P.A. Ozer et al. / Journal of Diabetes and Its Complications 23 (2009) 244–248 Table 2 Serum glucose, creatinine, and HbA1c levels of patients Group 1 (n=20) Group 2 (n=20) Group 3 (n=20) Table 4 Classification of the patients according to their current treatment type Mean glucose (mg/dl) Mean HbA1c (g/dl) Mean Creatinine (mg/dl) 220.1±77.61 242.4±84.5 189.35±103.22 9.2±1.96 8.1±2.3 8.1±2.6 0.9±0.3 0.7±0.14 0.7±0.12 (total cholesterol, triglyceride, LDL, HDL), glucosylated hemoglobin (HbA1c), fasting blood glucose, creatinine levels, and the correlation of these levels to the clinical findings. P values b.05 were considered statistically significant. 3. Results The demographic characteristics of the patients and severity of their retinopathies are given in Table 1. Serum glucose, creatinine, and HbA1c levels of patient are given in Table 2. Serum lipid levels of the patients are given in Table 3. There was no difference between Groups 1 and 2 in terms of mean follow-up time and between three groups in terms of presence of hypertension (PN.05). The clinical judgment from fundus examination of the patients was not different from OCT and FFA findings. Fifty percent of the patients in Group 1 had PDR, whereas 25% of those in Group 2 had PDR. No significant difference was found among Groups 1 and 2 in terms of severity of retinopathy (PN.05). Duration of diabetes was 14 (±12) years in Group 1, 10 (±7) years in Group 2, and 5 (±4) years in Group 3. It was significantly shorter in Group 3 than in Groups 1 and 2. Patients in Group 1 had significantly longer duration of diabetes than in Groups 2 and 3 (Pb.05). There was no significant difference between total cholesterol, triglyceride, LDL, HDL, and HbA1c levels of the patients in three groups. Creatinine levels in patients with chronic diabetic macular edema and plaque-like hard exudates were significantly higher than the other two groups (Pb.05). Although there was no significant correlation between levels of fasting blood glucose and HbA1c, levels of HbA1c were significantly higher in all three groups from the baseline-normal limits (Pb.05). The correlation of serum Table 3 Serum lipid levels of the patients Mean total cholesterol (mg/dl) Group 1 (n=20) Group 2 (n=20) Group 3 (n=20) Mean triglyceride (mg/dl) Mean HDL (mg/dl) Mean LDL (mg/dl) 233±120.2 43.5±11.6 126.6±37.3 211.4±52.7 213.5±138.9 47.2±14.2 111.1±35.8 212.2±37.6 187.5±102.3 44.6±8.9 114.3±36.6 206.3±51.70 Group 1 (n=20) Group 2 (n=20) Group 3 (n=20) Insulin (n=33) Oral antidiabetics (n=27) 14 9 10 6 11 10 lipid levels and the clinical presentation of macular edema are found to be independent from age, gender, duration of diabetes, and HbA1c levels. Classification of the patients according to their current treatment type is given in Table 4. No significant difference exists among groups when their current treatment type is concerned. HbA1c, creatinine, total cholesterol, HDL, LDL, and triglyceride levels did not show any difference among two treatment types (PN.05). 4. Discussion Association of lipid fractions with macrovascular complications of diabetes (e.g., coronary artery disease) has been studied in many studies, but a few number of them were interested in the association of serum lipids with microvascular complications such as DR, and the available results are conflicting (Avci & Kaderli, 2006; Camera & Hopps, 2007; Chew & Klein, 1996; Dornan et al., 1982; Early Treatment of Diabetic Retinopathy Study Research Group, 1985; Early Treatment of Diabetic Retinopathy Study Research Group, 1991; El Haddad & Saad, 1998; Ferris & Chew, 1996; Klein & Klein, 1984; Klein & Klein, 1999; Kordonouri & Danne, 1996; Larsson & Alm, 1999; Marshall & Garg, 1993; Mouton & Gill, 1988; Rema & Mohan, 1984; Sinav & Onelge, n.d; Sjolie & Stephenson, 1997; Weber & Burger, 1986). This conflict is thought to arise from the heterogeneity in subject selection with variable inclusion criteria and differences in the methodology of assessment and classification of DR. Dornan et al. (1982) first showed the association of LDL cholesterol in subjects with DR in a landmark study. Klein and Klein (1999) reported an association of unadjusted serum cholesterol with severity of hard exudates in the macula. Rema et al contributed to the literature with a study in which the association of LDL cholesterol and diabetic macular edema was investigated, and with another study in which the association between total cholesterol, LDL cholesterol, and non-HDL cholesterol with diabetic macular edema (DME) in subjects with Type 2 diabetes was searched (Camera & Hopps, 2007; Early Treatment of Diabetic Retinopathy Study Research Group, 1985; El Haddad & Saad, 1998; Kordonouri & Danne, 1996; Larsson & Alm, 1999; Marshall & Garg, 1993; Mouton & Gill, 1988; Sinav & Onelge, n.d; Sjolie & Stephenson, 1997; Rema & Srivastava, 2006; Van Leiden & Dekker, 2002; Weber & Burger, 1986). Results of the ETDRS study and the study of Van Leiden et al. also show a close relationship of total cholesterol and LDL cholesterol levels with retinal hard P.A. Ozer et al. / Journal of Diabetes and Its Complications 23 (2009) 244–248 exudate formation and severity of retinopathy (Camera & Hopps, 2007; Chew & Klein, 1996; Early Treatment of Diabetic Retinopathy Study Research Group, 1985; Early Treatment of Diabetic Retinopathy Study Research Group, 1991; El Haddad & Saad, 1998; Kordonouri & Danne, 1996; Larsson & Alm, 1999; Marshall & Garg, 1993; Mouton & Gill, 1988; Sinav & Onelge, n.d; Rema & Mohan, 1984; Sjolie & Stephenson, 1997; Van Leiden & Dekker, 2002; Weber & Burger, 1986). In a study conducted on Type 2 diabetic patients in a South Indian population, non-HDL cholesterol and total cholesterol levels were significantly higher in patients with DR, and these levels were also significantly higher in patients with DME than the ones without. Since this correlation is found to be independent from age, gender, and the duration of diabetes, but significantly dependent on HbA1c levels, the importance of glycemic control was the point in the study (Rema & Srivastava, 2006). As we also investigated the correlation of serum lipid levels and DR, particularly the effect of serum lipids on macular edema, our study is similar to these previous studies. Since diabetic patients without any retinopathy and patients with chronic macular edema with plaque-like hard exudates in association to DR are involved as the control groups, our study is supposed to be different from the previous studies in the literature. The mechanisms by which high serum lipids cause the development and progression of DR are not fully understood. It has been postulated that an increase in blood viscosity and alterations in the fibrinolytic system occur in hyperlipidemia and lead to the formation of hard exudates (Freyberger & Schifferdecker, 1994). Incorporation of triglycerides into the cell membrane may lead to changes in membrane fluidity and leakage of plasma constituents in the retina (Ebeling & Koivisto, 1997). This results in hemorrhage and edema in the retina. Also, high lipid levels are known to cause endothelial dysfunction (Langeler & Snelting-Havinga, 1989; Rangaswamy & Penn, 1997). In animal models, it has been shown that endothelial dysfunction in the diabetic vasculature results in blood–retinal barrier breakdown (Joussen & Murata, 2001; Joussen & Poulaki, 2002). This endothelial dysfunction is the common aspect of DR and nephropathy that was documented in many of the previous studies (Bergner & Lenz, 2006; Izzedine & Fongoro, 2001). Progressive glomerulosclerosis after endothelial injury results in microalbuminuria in diabetic patients, which is marked as the first sign of glomerular injury (Izzedine & Fongoro, 2001; Paueksakon & Revelo, 2002). Serum creatinine levels and creatinine clearance are also important landmarks of renal function reflecting the dysfunction in renal endothelial cells. It is also well known that retinopathy, especially the presence of proliferative DR, is an independent predictor for nephropathy (El-Asrar & AlRubeaan, 2001). Plasma triglycerides were reported to be an important predictor of renal failure in Type 2 DM (Colhoun & Lee, 2001). The primary aim of our study was to investigate the effect of serum lipid levels on the severity of 247 maculopathy, but due to this close relationship, we also investigated the correlation of serum creatinine levels with the maculopathy severity. As far as we know, this was the first study that searched the association of serum creatinine levels of patients with different stages of diabetic maculopathies with the maculopathy severity. In our study, the serum creatinine levels were found to be higher in patients with chronic macular edema. This may be explained with the concomitant pathology in diabetic vasculature in kidneys and retina, which is microangiopathy. In our study, we were not able to show a correlation between serum lipid levels and macular edema. This is probably due to the small sample size of our groups. The correlation of serum lipid levels and the clinical presentation of macular edema are found to be independent from age, gender, duration of diabetes, and HbA1c levels. It may also be related to the limited number of cases in the study. But the effect of the duration of diabetes on macular edema presentation was found to be significant. Patients with longer duration of diabetes presented frequently with chronic macular edema with hard exudates. There was no literature about serum lipid profiles of the patients with DR under different treatment modalities. In our study, any effect of current treatment modality (oral antidiabetics or insulin) on macular edema status was not shown. 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