September 2011
Volume 52, Issue 10
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Clinical and Epidemiologic Research  |   September 2011
Differential Association of Serum Lipids with Diabetic Retinopathy and Diabetic Macular Edema
Author Affiliations & Notes
  • Rehab Benarous
    From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia;
  • Muhammad B. Sasongko
    From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia;
    the Department of Ophthalmology, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia; and
  • Salmaan Qureshi
    From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia;
  • Eva Fenwick
    From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia;
  • Mohamed Dirani
    From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia;
  • Tien Y. Wong
    From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia;
    the Singapore Eye Research Institute, National University of Singapore, Singapore.
  • Ecosse L. Lamoureux
    From the Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia;
    the Singapore Eye Research Institute, National University of Singapore, Singapore.
  • Corresponding author: Ecosse L. Lamoureux, Principal Research Fellow, Department of Ophthalmology, University of Melbourne, 32 Gisborne Street, East Melbourne 3002, Victoria, Australia; ecosse@unimelb.edu.au
Investigative Ophthalmology & Visual Science September 2011, Vol.52, 7464-7469. doi:10.1167/iovs.11-7598
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      Rehab Benarous, Muhammad B. Sasongko, Salmaan Qureshi, Eva Fenwick, Mohamed Dirani, Tien Y. Wong, Ecosse L. Lamoureux; Differential Association of Serum Lipids with Diabetic Retinopathy and Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2011;52(10):7464-7469. doi: 10.1167/iovs.11-7598.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To assess the association of serum lipids with diabetic retinopathy (DR), diabetic macular edema (DME), and macular thickness in adults with diabetes.

Methods.: Diabetic patients aged ≥18 years were prospectively recruited from specialized eye clinics in Melbourne, Australia. Fasting total-C (cholesterol), triglyceride, HDL-C, non-HDL-C, and LDL-C were assessed. DR was graded from fundus photographs and classified into mild, moderate, severe nonproliferative, and proliferative DR and separately graded for the presence of DME, including clinically significant macular edema (CSME). Macular thickness was assessed using optical coherence tomography (OCT).

Results.: A total of 500 participants (median age, 65 years) were examined. DR, DME, and CSME were present in 321 (66.2%), 149 (33.0%), and 68 (15.0%) patients, respectively. Serum lipid levels were not related to DR or DME. In multivariate models adjusted for traditional risk factors and lipid medications, persons with higher total-, LDL-, and non-HDL-C were more likely to have CSME (odds ratio of 1.54, 1.49, and 1.63 per 1-SD increase, respectively; all P < 0.05). No association was found for serum lipids with macular thickness, as assessed by OCT. The pattern of these associations remained similar in both type 1 and type 2 diabetes, although it was statistically significant only in type 2 diabetes.

Conclusions.: Serum lipids are independently associated with the CSME, but not with DR, mild or moderate DME, or macular thickness. These data reflect the different impact of hyperlipidemia in the pathogenesis of DR and DME and may explain the discrepancies in previous studies.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes. 1,2 Diabetic macular edema (DME), which can occur at any stage of DR, is now the major cause of vision loss and the target of a range of new therapies, such as intraocular administration of anti-vascular endothelial growth factor treatments. 3  
Although landmark studies have shown that intensive glycemic and blood pressure control can substantially reduce the onset and progression of DR, 4,5 the contribution of lipids to the pathogenesis of DR and DME has been less clear. 6 8 Previous studies have shown a stronger association of serum lipids with DME than DR, per se, 9,10 yet the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study reported the benefits of fenofibrate in slowing the progression of DR, 11 although this trial did not specifically evaluate the effect of fenofibrate on DME. 
The relationship of lipids with DR and DME deserves further investigation for two reasons. First, only one study has reported the detailed assessment of the association of serum lipids with DR and DME severity 9 and only two reports have examined this relationship specifically with proliferative diabetic retinopathy (PDR) or the more severe spectrum of macular edema, clinically significant macular edema (CSME). 10,12 Second, no study has examined whether lipids have an effect on objective measurement of early retinal pathology, such as macular thickness quantified using optical coherence tomography (OCT). 13  
Thus, we prospectively recruited a large clinical sample of diabetic patients with the spectrum of DR and DME and investigated the association of serum lipids, including serum total cholesterol, triglycerides (TGs), LDL-C, HDL-C, and non-HDL-C with the presence and severity of DR, DME, and macular thickness (determined by OCT), in patients with type 1 and 2 diabetes. 
Methods
Study Population
Five hundred English-speaking adults with diabetes (391 type 2, 79.5%) aged 18 years or older were prospectively recruited from general and specialized eye clinics at the Royal Victorian Eye and Ear Hospital, Victoria, Australia, from March 2009 to July 2010 as part of the Diabetes Management Project. All participants were free of significant hearing and cognitive impairment and lived independently in the community. Written informed consent was obtained from all participants. The study was approved by the Human Research and Ethics Committee and adhered to the tenets of the Declaration of Helsinki. 
Assessment of Diabetic Retinopathy
DR was graded from two-field fundus photographs (CR6-45NM, Canon Inc., Tokyo, Japan), according to the modified Airlie House classification system. We categorized the severity of DR as no DR (Early Treatment of Diabetic Retinopathy Study [ETDRS] levels 10–15), mild nonproliferative DR (NPDR; level 20), moderate NPDR (levels 31–43), severe NPDR (levels 53–60), and PDR (levels 61–80). 
DME was graded from stereoscopic fundus photographs and was confirmed by OCT. DME was considered present if there was some visible retinal thickening or hard exudates in the posterior pole. If present, DME was further classified as mild (retinal thickening or hard exudate distant from the macula), moderate (retinal thickening or hard exudate approaching the center of the macula), or CSME (retinal thickening within a circle of 1-mm diameter at the center of the macula). 
Assessment of Macular Thickness
OCT (Stratus Model 3000; Carl Zeiss Meditec Inc., North Ryde, NSW, Australia) was used to measure macular thickness. Fast macular scans with retinal map analyses were performed for both eyes. Four measurements were recorded: (1) central macular thickness (CMT), defined as the central circular zone of 1 mm diameter of the scan; (2) inner macular thickness (IMT), defined as the mean retinal thickness within the central 3 mm surrounding the central circular zone; (3) outer macular thickness (OMT), defined as the mean retinal thickness within the central 6 mm surrounding the central circular zone; and (4) total macular volume (TMV). Right eye measurement was used for this analysis (Pearson correlation for right and left >0.5). 
Blood and Urine Chemistry
Fasting (≥8 hours) blood samples were collected for analysis of blood glucose, glycated hemoglobin (GHb), and lipids (total-, HDL-, and LDL-C [cholesterol] and triglycerides). Fasting plasma glucose and serum lipids including total, HDL-C and triglycerides, were estimated with a chemistry analyzer (Modular P; Roche Diagnostics; Mannheim, Germany). Non-HDL-C was calculated by subtracting HDL-C from total-C. The Friedewald formula was used to calculate LDL-C, if plasma triglyceride concentrations were less than or equal to 4.5 mmol/L (400 mg/dL). In participants with triglyceride concentrations >4.5 mmol/L, LDL-C measurements were not calculated. 
A 50-mL midstream urine sample was collected into 50-mL specimen containers, to determine the albumin creatinine ratio (ACR). All blood and urine analyses were performed at Melbourne Pathology (Melbourne, Australia), with individual results electronically delivered through a password-protected program. The laboratory is accredited to the International Standard ISO15189 (Medical Laboratories) and is certified by NATA (National Association of Testing Authorities). 
Assessment of Other Risk Factors
Each participant underwent a comprehensive assessment that included a range of clinical, biochemical, and anthropometric measurements and a series of validated questionnaires on lifestyle, diet, psychosocial factors, and quality of life. Key covariates included age, sex, duration of diabetes (years), diabetic medication use, use of antihypertensive medications, use of lipid-lowering medications, GHb level (percentage), blood pressure (mm Hg), body mass index (BMI; kilograms divided by height in meters squared), waist circumference (WC; in centimeters), ACR, and smoking status 
Statistical Analysis
Participants' characteristics with and without DR, DME, and CSME were compared by using the χ2 statistic for proportions, and a t-test or Mann–Whitney U test for means or median (Intercooled STATA version 10.1 for Windows; StataCorp., College Station, TX). Serum lipids were assessed categorically (in quintiles) and continuously (per standard deviation change). The four measures of macular thickness were assessed as continuous variables. Normality was checked, and data were transformed as appropriate. Person data were used for DR, DME, and CSME based on the worse eye. Multinomial and ordinal logistic regression models were performed to assess associations between serum lipids and severity of DR (mild, moderate, severe NPDR, and PDR) or DME (mild, moderate, and CSME). A binomial logistic regression model was used to assess the association between serum lipids and CSME. Association between serum lipids and macular thickness was examined using generalized linear models. We initially adjusted for age and sex (model 1) and additionally for diabetes duration, GHb, SBP, BMI, use of diabetes medications, use of lipid-lowering medications, and insulin usage (model 2). Covariates included in the models were either categorical or continuous (per standard deviation changes for age, SBP, and BMI; per year for diabetes duration; and per percent for GHb level). 
Results
Of the 500 participants, 436 (87.2%) had type 2 and 64 (12.8%) had type 1 diabetes. Among 492 with gradable fundus photographs, 321(65.2%) had any DR and 171 (34.8%) had no signs of DR. In those with DR, 22 (4.5%) had mild NPDR, 139 (28.3%) had moderate NPDR, 26 (5.3%) had severe NPDR, and 134 (27.2%) had PDR. Of those with DR, 149 (33.0%) and 68 (15.1%) had DME and CSME, respectively. The participants' characteristics stratified for DR, DME, or CSME status are shown in Table 1. Participants with DR and DME were younger, had a longer duration of diabetes, and had higher GHb and increased macular thickness and volume (all P < 0.001) than did those without. Serum lipid levels were similar in persons with DR or DME compared with those without. However, total-, non-HDL-, and LDL-C were significantly higher in participants with CSME than in those without CSME (all P < 0.001). 
Table 1.
 
Participant's Characteristics According to Diabetic Retinopathy and Macular Edema Presence
Table 1.
 
Participant's Characteristics According to Diabetic Retinopathy and Macular Edema Presence
DR DME CSME
Absent Present Absent Present Absent Present
Characteristics (%)
n (%) 171 (34.8) 321 (65.2) 302 (66.9) 149 (33.0) 383 (84.9) 68 (15.0)
Male 57.5 71.7 61.2 76.5* 65.8 69.1
Current smoker 12.1 9.7 10.9 9.52 10.5 10.5
Use of insulin 22.2 53.6† 37.0 55.0* 39.9 60.3*
Use of oral hypoglycemic agent 70.6 73.6 72.6 74.5 70.5 88.1*
Use of lipid-lowering medication
Statins 10.3 8.2 9.2 12.3 11.5 13.4
Fenofibrate 8.0 9.0 7.3 7.10 5.5 7.2
Use of anti-hypertensive medication 26.5 23.2 22.1 29.5 24.02 27.94
Characteristics, Mean (SD)
Age, y 68.0 (17.0) 63.0 (15.0)* 64.9 (12.6) 61.9 (11.5)* 64.6 (12.0) 60.2 (11.1)*
BMI, kg/m2 30.5 (6.6) 30.9 (6.0) 33.9 (22.3) 30.5 (12.0) 33.2 (21.0) 30.3 (6.1)
WC, cm 104.7 (17.5) 107.7 (15.3) 104 (19.8) 103 (20.3) 107 (43.4) 103 (21.6)
SBP, mm Hg 138.6 (18.6) 141.1 (18.9) 139 (18.7) 141 (19.3) 139.7 (18.8) 141 (1963)
Duration of diabetes, y‡ 8.0 (9.0) 18.0 (12.0)* 14.5 (11.5) 17.8 (10.2)* 15.5 (11.6) 16.5 (8.2)
GHb, % 7.3 (1.3) 8.0 (1.5)* 7.5 (1.3) 8.1 (1.6)* 7.6 (1.4) 8.3 (1.7)*
CMT, μm 215.5 (38.5) 236.0 (85.0)* 217.0 (50.0) 250.5 (94.1)* 241.9 (78.3) 301.7 (117.9)*
IMT, μm 261.0 (29.9) 279.4 (52.5)* 269.2 (52.5) 288.9 (60.9)* 274.8 (54.7) 323.6 (81.5)*
OMT, μm 228.5 (24.8) 250.9 (43.8)* 239.5 (33.3) 277.5 (52.5)* 244.0 (35.8) 291.9 (62.2)*
TMV, mm3 6.7 (0.7) 7.5 (1.4)* 6.9 (1.0) 8.0 (1.5)* 7.1 (1.1) 8.4 (1.8)*
Cholesterol, mmol/L 4.8 (1.2) 4.6 (1.3) 4.6 (1.3) 4.7 (1.3) 4.6 (1.2) 5.2 (1.4)*
TGs, mmol/L‡ 1.7 (1.0) 1.9 (1.5) 1.8 (1.2) 1.9 (1.3) 1.8 (1.1) 2.1 (1.8)
HDL-C, mmol/L 1.4 (0.5) 1.3 (0.4)† 1.4 (0.4) 1.3 (0.4) 1.3 (0.4) 1.3 (0.5)
Non-HDL-C, mmol/L 3.3 (1.3) 3.3 (1.3) 3.2 (1.3) 3.4 (1.2) 3.2 (1.2) 3.8 (1.3)*
LDL-C, mmol/L 2.5 (1.0) 2.4 (1.1) 2.4 (1.0) 2.6 (1.1) 2.4 (1.0) 2.9 (1.2)*
LDL-C/HDL-C 2.0 (1.4) 1.9 (0.9) 1.8 (1.2) 2.0 (1.0)† 1.8 (1.1) 2.3 (1.1)*
Chol/HDL-C 3.6 (1.4) 3.7 (1.4) 3.5 (1.3) 3.8 (1.3)† 3.5 (1.3) 4.2 (1.5)*
Table 2 shows the association of serum lipids with DR severity. After adjustment for age and sex (model 1), serum lipids were not associated with increasing severity of DR (Table 2). 
Table 2.
 
Association of Serum Lipids with the Severity of DR
Table 2.
 
Association of Serum Lipids with the Severity of DR
Serum Lipids (Per SD increase) Mild NPDR OR (95% CI) Moderate NPDR OR (95% CI) Severe NPDR OR (95% CI) PDR OR (95% CI) P trend
Model 1*
    Cholesterol (1.3), mmol/L 1.00 (0.63–1.59) 0.77 (0.60–0.99) 1.18 (0.79–1.77) 0.86 (0.67–1.10) 0.26
    Triglyceride (1.0), mmol/L 1.49 (0.97–2.45) 1.00 (0.75–1.34) 1.09 (0.71–1.67) 1.07 (0.81–1.41) 0.72
    HDL-C (1.1), mmol/L 1.02 (0.66–1.58) 0.88 (0.69–1.13) 0.86 (0.51–1.43) 0.93 (0.72–1.20) 0.36
    Non HDL-C (1.3), mmol/L 0.99 (0.62–1.59) 0.80 (0.62–1.03) 1.23 (0.83–1.84) 0.87 (0.68–1.12) 0.39
    LDL-C (1.3), mmol/L 0.77 (0.46–1.31) 0.77 (0.60–0.98) 1.18 (0.79–1.76) 0.88 (0.69–1.12) 0.38
    LDL-C/HDL-C (1.2) 0.82 (0.45–1.47) 0.73 (0.54–0.98) 1.11 (0.78–1.58) 0.88 (0.67–1.16) 0.41
    Chol/HDL-C (1.2) 0.88 (0.51–1.52) 0.80 (0.61–1.05) 1.26 (0.84–1.88) 0.99 (0.76–1.27) 0.89
Model 2†
    Cholesterol (1.3), mmol/L 1.02 (0.60–1.74) 0.73 (0.53–1.01) 1.16 (0.72–1.86) 0.79 (0.57–1.11) 0.20
    Triglyceride (1.0), mmol/L 1.55 (0.97–2.47) 1.02 (0.71–1.48) 1.12 (0.69–1.83) 1.16 (0.81–1.66) 0.48
    HDL-C (1.1), mmol/L 0.97 (0.61–1.56) 0.89 (0.67–1.19) 0.90 (0.51–1.56) 0.90 (0.66–1.24) 0.34
    Non HDL-C (1.3), mmol/L 1.05 (0.61–1.80) 0.76 (0.55–1.05) 1.22 (0.76–1.96) 0.83 (0.59–1.16) 0.33
    LDL-C (1.3), mmol/L 0.75 (0.41–1.36) 0.69 (0.50–0.95) 1.06 (0.67–1.70) 0.76 (0.55–1.06) 0.14
    LDL-C/HDL-C (1.2) 0.86 (0.48–1.55) 0.66 (0.46–0.96) 1.09 (0.69–1.75) 0.85 (0.59–1.21) 0.41
    Chol/HDL-C (1.2) 0.93 (0.51–1.70) 0.74 (0.53–1.04) 1.30 (0.81–2.07) 1.03 (0.74–1.43) 0.64
Table 3 shows the association of serum lipids with the severity of DME. Except for LDL-C which was associated with increasing severity of DME (P trend = 0.02), no other lipid measure was associated (model 1). However, after adjustment for traditional risk factors and lipid-lowering medications, the association between serum lipids and DME lost its significance (P trend = 0.06; Table 3). 
Table 3.
 
Association of Serum Lipids with the Severity of DME
Table 3.
 
Association of Serum Lipids with the Severity of DME
Serum Lipids (Per SD Increase) Mild DME OR (95% CI) Moderate DME OR (95% CI) CSME OR (95% CI) P trend
Model 1*
    Cholesterol (1.3), mmol/L 0.90 (0.63–1.29) 0.81 (0.54–1.19) 1.41 (1.09–1.82) 0.08
    Triglyceride (1.0), mmol/L 0.92 (0.62–1.37) 0.79 (0.49–1.29) 1.11 (0.86–1.43) 0.72
    HDL-C (1.1), mmol/L 1.02 (0.70–1.50) 0.96 (0.64–1.42) 1.04 (0.78–1.38) 0.94
    Non HDL-C (1.3), mmol/L 0.89 (0.61–1.29) 0.81 (0.55–1.21) 1.40 (1.10–1.81) 0.07
    LDL-C (1.3), mmol/L 0.89 (0.61–1.29) 0.85 (0.58–1.26) 1.50 (1.17–1.93) 0.02
    LDL-C/HDL-C (1.2) 0.96 (0.64–1.46) 0.75 (0.46–1.22) 1.34 (1.04–1.71) 0.06
    Chol/HDL-C (1.2) 0.96 (0.66–1.39) 0.76 (0.49–1.18) 1.41 (1.08–1.84) 0.08
Model 2†
    Cholesterol (1.3), mmol/L 0.74 (0.45–1.09) 0.84 (0.52–1.18) 1.50 (1.08–1.96) 0.07
    Triglyceride (1.0), mmol/L 0.96 (0.59–1.48) 0.78 (0.48–1.25) 1.00 (0.74–1.36) 0.77
    HDL-C (1.1), mmol/L 0.79 (0.49–1.27) 0.88 (0.57–1.37) 1.18 (0.86–1.62) 0.60
    Non HDL-C (1.3), mmol/L 0.77 (0.46–1.14) 0.79 (0.51–1.21) 1.41 (1.04–1.90) 0.10
    LDL-C (1.3), mmol/L 0.69 (0.45–1.09) 0.83 (0.55–1.25) 1.55 (1.15–2.09) 0.06
    LDL-C/HDL-C (1.2) 0.88 (0.54–1.45) 0.74 (0.44–1.26) 1.37 (1.06–1.77) 0.05
    Chol/HDL-C (1.2) 0.94 (0.61–1.46) 0.75 (0.46–1.22) 1.43 (1.04–1.97) 0.10
Table 4 shows the associations of serum lipids with CSME. After adjustment for age and sex, per SD increase in total-C (odd ratio [OR], 1.45; 95% confidence interval [CI], 1.13–1.86; P = 0.003), non-HDL-C (OR, 1.45; 95% CI, 1.13–1.86; P = 0.003), LDL-C (OR, 1.54; 95% CI, 1.21–1.98; P = 0.001), LDL-C/HDL-C (OR, 1.37; 95% CI, 1.07–1.75; P = 0.014), and total-C/HDL-C (OR, 1.46; 95% CI, 1.13–1.89; P = 0.004) were strongly associated with having CSME. These associations persisted after further adjustment for duration of diabetes, GHb, SBP, BMI, and use of insulin, oral hypoglycemia, and lipid-lowering medications. Stratification of these results by sex and diabetes type showed that our findings were similar for the women and the men, or in type 1 and type 2 diabetes, except for non-HDL-C with regard to having CSME. However, these associations were only significant in type 2 diabetes (Supplementary Tables S4–S6). 
Table 4.
 
Association of Serum Lipids with CSME
Table 4.
 
Association of Serum Lipids with CSME
Serum Lipids At Risk (n) Model 1 OR (95% CI) P Model 2 OR (95% CI) P
Cholesterol, mmol/L
    1st quintile, ≤3.5 97 1.00 1.00
    2nd quintile, 3.6–4.2 95 1.41 (0.53–3.73) 1.06 (0.38–3.30)
    3rd quintile, 4.3–4.7 100 1.21 (0.45–3.24) 1.36 (0.46–3.96)
    4th quintile, 4.8–5.6 92 2.56 (1.02–6.40) 4.34 (1.57–12.0)
    5th quintile, ≥5.7 83 2.88 (1.12–7.12) 0.006* 3.48 (1.26–9.64) 0.001*
    Per SD (1.3) increase 1.45 (1.13–1.86) 0.003 1.54 (1.15–2.07) 0.003
Triglyceride, mmol/L
    1st quintile, ≤1.0 110 1.00 1.00
    2nd quintile, 1.1–1.4 95 1.38 (0.55–3.47) 1.28 (0.45–3.64)
    3rd quintile, 1.5–1.8 85 2.78 (1.19–6.52) 2.60 (1.00–6.74)
    4th quintile, 1.9–2.5 92 1.66 (0.68–4.05) 1.72 (0.64–4.61)
    5th quintile, ≥2.6 84 1.72 (0.70–4.20) 0.21* 1.47 (0.53–4.08) 0.37*
    Per SD (1.1) increase 1.14 (0.89–1.47) 0.30 1.04 (0.78–1.40) 0.74
HDL-C, mmol/L
    1st quintile, ≤1.0 100 1.00 1.00
    2nd quintile, 1.1–1.2 101 1.11 (0.49–2.51) 1.11 (0.44–2.81)
    3rd quintile, 1.3–1.4 85 1.28 (0.55–3.01) 1.46 (0.56–3.76)
    4th quintile, 1.5–1.7 94 1.37 (0.60–3.14) 1.29 (0.50–3.32)
    5th quintile, ≥1.8 84 0.94 (0.36–2.43) 0.84* 1.33 (0.46–3.84) 0.52*
    Per SD (1.0) increase 1.04 (0.79–1.38) 0.77 1.21 (0.89–1.65) 0.22
Non HDL-C, mmol/L
    1st quintile, ≤2.1 94 1.00 1.00
    2nd quintile, 2.2–2.7 94 2.82 (0.95–8.32) 1.74 (0.52–5.78)
    3rd quintile, 2.8–3.2 96 2.27 (0.75–6.85) 1.99 (0.63–6.26)
    4th quintile, 3.3–4.1 88 3.37 (1.14–9.92) 3.64 (1.18–11.2)
    5th quintile, ≥4.2 92 4.82 (1.72–13.5) 0.003* 4.95 (1.63–15.1) 0.001*
    Per SD (1.4) increase 1.45 (1.13–1.86) 0.003 1.49 (1.11–1.99) 0.007
LDL-C, mmol/L
    1st quintile, ≤1.6 97 1.00 1.00
    2nd quintile, 1.7–2.0 107 3.13 (0.98–9.96) 3.82 (1.14–12.8)
    3rd quintile, 2.1–2.4 77 3.18 (0.93–10.9) 2.32 (0.59–9.03)
    4th quintile, 2.5–3.2 83 4.29 (1.33–13.8) 5.38 (1.61–17.9)
    5th quintile, ≥3.3 86 6.63 (2.15–10.5) 0.001* 8.02 (2.42–26.5) <0.001*
    Per SD (1.4) increase 1.54 (1.21–1.98) 0.001 1.63 (1.22–2.19) <0.001
LDL-C/HDL-C
    1st quintile, ≤1.1 95 1.00 1.00
    2nd quintile, 1.2–1.5 92 1.49 (0.45–4.92) 1.20 (0.35–4.12)
    3rd quintile, 1.6–2.0 84 3.14 (1.07–9.24) 2.39 (0.74–7.72)
    4th quintile, 2.1–2.6 100 3.81 (1.32–10.9) 3.18 (1.04–9.78)
    5th quintile, ≥2.7 78 5.26 (1.82–15.2) <0.001* 4.89 (1.54–15.5) 0.001*
    Per SD (1.2) increase 1.37 (1.07–1.75) 0.014 1.41 (1.10–1.82) 0.008
Chol/HDL-C
    1st quintile, ≤2.5 97 1.00 1.00
    2nd quintile, 2.6–3.1 99 2.20 (0.71–6.75) 1.39 (0.42–4.66)
    3rd quintile, 3.2–3.8 86 3.95 (1.37–11.4) 3.08 (1.00–9.53)
    4th quintile, 3.9–4.7 91 2.83 (0.94–8.53) 2.47 (0.76–8.08)
    5th quintile, ≥4.8 92 5.59 (1.97–15.9) 0.001* 4.78 (1.51–15.1) 0.003*
    Per SD (1.2) increase 1.46 (1.13–1.89) 0.004 1.49 (1.09–2.03) 0.012
No serum lipid measure was associated with any of the macular thickness parameters (Supplementary Table S2). 
Discussion
In this large clinical sample of adults with diabetes, we found that serum lipids were not associated with the presence and severity of DR, mild or moderate DME, or macular thickness. In contrast, serum lipids (total-C, LDL-C, non-HDL-C, LDL-C/HDL-C, and total-C/HDL-C) were independently associated with CSME, after adjustment for traditional DR risk factors and lipid-lowering medications. 
The lack of association of serum lipids with both the presence and severity of DR in this study is compatible with previous data from the Multi-ethnic Study of Atherosclerosis (MESA), which show no association between serum lipids, including total-C, LDL-C, and HDL-C and DR, 7 and the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). 14 On the contrary, our findings of an association between serum lipids and CSME confirm previous reports that have specifically evaluated this endpoint. 9,10 For example, data from the Diabetes Control and Complication Trial (DCCT) 4 demonstrated that LDL-C and total-C/HDL-C were associated with increased risk for developing CSME. Recent evidence from the Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study also demonstrated that patients with CSME, but not DME, had elevated total-, non HDL-, and LDL-C. 10  
The association between serum lipids and CSME is biologically plausible. 9 Several proposed mechanisms discussed in earlier reports include the direct involvement of serum lipids in endothelium dysfunction 15,16 which subsequently result in the breakdown of the blood retinal barrier leading to exudation of serum lipids and lipoproteins to intercellular space in the retina. 10,17 However, although DR and CSME share some similar pathogenesis, our study demonstrated that the association of serum lipids with DR was different from that with CSME. Whereas serum lipids were not associated with DR, in contrast, we found strong associations with CSME. 
We speculate that serum lipids may have a strong influence only in the severe forms of diabetic microvascular eye endpoint. In support of this, our data showed that serum lipids were not associated with macular thickness and volume in this population. These findings may provide additional insight that serum lipids are involved in the pathogenesis of DME only via exudation of lipids through damaged retinal vasculature, which occurs at a later stage, but may not cause direct injury to the endothelium and consequent damage to the blood–retinal barrier, which can occur at an earlier stage. 18,19 Consistent with this hypothesis, a previous study found that there was no association between serum lipids and development of retinopathy in nondiabetics, 20 indicating the importance of existing damage in retinal vasculature for lipids to exhibit their harmful effect on the retina. Future work is obviously needed in this area. 
Our study findings have clear clinical implications. The difference in the association of serum lipids with DR and CSME suggests that hyperlipidemia may have a different impact on those disorders. We have speculated that serum lipids are involved in the later, more severe stages than in earlier stages; thus, dyslipidemia may have a more direct impact on CSME than on DR. This finding may help to explain the discrepancy in previous studies and suggests that lipid-targeting therapies may show more benefit in slowing the progression to the severe stage than in preventing the development of DR. This notion is supported by the data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and ACCORD-Eye trials, which showed that the use of lipid-lowering medication slowed the progression of DR, but was not related to incident DR. 11,21 These two studies were, however, large prospective clinical trials, and information about the impact of lipid-lowering therapy on DME and CSME has not been presented. This area of research needs to be further investigated in the future. 
Our study's strengths include the large clinical sample of diabetic patients with differing levels of DR, the assessment of DR by grading retinal photographs according to standardized protocols, assessment of DME by OCT, detailed and comprehensive clinical examination, and a patient sample with typical characteristics of other diabetic populations, with DR showing strong associations with duration of diabetes and GHb level, which support the generalizability of our findings. However, some limitations are also noted. First, the cross-sectional nature of the study did not allow us to assess the temporal sequence of these associations. Second, DR was graded from two-field instead of seven-field retinal photographs, as were used in large clinical trials such as the ETDRS. This method may have underestimated the presence of DR. However, since we did not find any association with DR, grading of two-field photographs is unlikely to have affected our findings. Third, there is a possibility of selection bias due to patients with resolved CSME after treatment being categorized as non-CSME. However, during the recruitment process, we also carefully reviewed and obtained detailed medical history, and we did not find such cases. Therefore, a selection bias in this regard was unlikely to occur. Finally, due to the small number of patients with type 1 diabetes in this study, no distinction was made between types 1 and 2 diabetes in the primary analysis. However, stratification for types 1 and 2 diabetes did not substantially change our findings (Supplementary Tables S4–S6). 
In conclusion, we have shown that serum lipids were largely associated with CSME, but not with the severity of DR, milder forms of DME, or subclinical macular thickness, suggesting a differential impact of dyslipidemia in the pathogenesis of DR and CSME. These findings may explain discrepancies found in previous studies and suggest that differing hyperlipidemia therapies targeting at DR and CSME are needed. 
Supplementary Materials
Table st1, DOC - Table st1, DOC 
Footnotes
 Supported by Australian Research Council (ARC) Linkage Grant LP0884108. The Centre for Eye Research Australia receives operational infrastructure support from the Victorian Government.
Footnotes
 Disclosure: R. Benarous, None; M.B. Sasongko, None; S. Qureshi, None; E. Fenwick, None; M. Dirani, None; T.Y. Wong, None; E.L. Lamoureux, None
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Table 1.
 
Participant's Characteristics According to Diabetic Retinopathy and Macular Edema Presence
Table 1.
 
Participant's Characteristics According to Diabetic Retinopathy and Macular Edema Presence
DR DME CSME
Absent Present Absent Present Absent Present
Characteristics (%)
n (%) 171 (34.8) 321 (65.2) 302 (66.9) 149 (33.0) 383 (84.9) 68 (15.0)
Male 57.5 71.7 61.2 76.5* 65.8 69.1
Current smoker 12.1 9.7 10.9 9.52 10.5 10.5
Use of insulin 22.2 53.6† 37.0 55.0* 39.9 60.3*
Use of oral hypoglycemic agent 70.6 73.6 72.6 74.5 70.5 88.1*
Use of lipid-lowering medication
Statins 10.3 8.2 9.2 12.3 11.5 13.4
Fenofibrate 8.0 9.0 7.3 7.10 5.5 7.2
Use of anti-hypertensive medication 26.5 23.2 22.1 29.5 24.02 27.94
Characteristics, Mean (SD)
Age, y 68.0 (17.0) 63.0 (15.0)* 64.9 (12.6) 61.9 (11.5)* 64.6 (12.0) 60.2 (11.1)*
BMI, kg/m2 30.5 (6.6) 30.9 (6.0) 33.9 (22.3) 30.5 (12.0) 33.2 (21.0) 30.3 (6.1)
WC, cm 104.7 (17.5) 107.7 (15.3) 104 (19.8) 103 (20.3) 107 (43.4) 103 (21.6)
SBP, mm Hg 138.6 (18.6) 141.1 (18.9) 139 (18.7) 141 (19.3) 139.7 (18.8) 141 (1963)
Duration of diabetes, y‡ 8.0 (9.0) 18.0 (12.0)* 14.5 (11.5) 17.8 (10.2)* 15.5 (11.6) 16.5 (8.2)
GHb, % 7.3 (1.3) 8.0 (1.5)* 7.5 (1.3) 8.1 (1.6)* 7.6 (1.4) 8.3 (1.7)*
CMT, μm 215.5 (38.5) 236.0 (85.0)* 217.0 (50.0) 250.5 (94.1)* 241.9 (78.3) 301.7 (117.9)*
IMT, μm 261.0 (29.9) 279.4 (52.5)* 269.2 (52.5) 288.9 (60.9)* 274.8 (54.7) 323.6 (81.5)*
OMT, μm 228.5 (24.8) 250.9 (43.8)* 239.5 (33.3) 277.5 (52.5)* 244.0 (35.8) 291.9 (62.2)*
TMV, mm3 6.7 (0.7) 7.5 (1.4)* 6.9 (1.0) 8.0 (1.5)* 7.1 (1.1) 8.4 (1.8)*
Cholesterol, mmol/L 4.8 (1.2) 4.6 (1.3) 4.6 (1.3) 4.7 (1.3) 4.6 (1.2) 5.2 (1.4)*
TGs, mmol/L‡ 1.7 (1.0) 1.9 (1.5) 1.8 (1.2) 1.9 (1.3) 1.8 (1.1) 2.1 (1.8)
HDL-C, mmol/L 1.4 (0.5) 1.3 (0.4)† 1.4 (0.4) 1.3 (0.4) 1.3 (0.4) 1.3 (0.5)
Non-HDL-C, mmol/L 3.3 (1.3) 3.3 (1.3) 3.2 (1.3) 3.4 (1.2) 3.2 (1.2) 3.8 (1.3)*
LDL-C, mmol/L 2.5 (1.0) 2.4 (1.1) 2.4 (1.0) 2.6 (1.1) 2.4 (1.0) 2.9 (1.2)*
LDL-C/HDL-C 2.0 (1.4) 1.9 (0.9) 1.8 (1.2) 2.0 (1.0)† 1.8 (1.1) 2.3 (1.1)*
Chol/HDL-C 3.6 (1.4) 3.7 (1.4) 3.5 (1.3) 3.8 (1.3)† 3.5 (1.3) 4.2 (1.5)*
Table 2.
 
Association of Serum Lipids with the Severity of DR
Table 2.
 
Association of Serum Lipids with the Severity of DR
Serum Lipids (Per SD increase) Mild NPDR OR (95% CI) Moderate NPDR OR (95% CI) Severe NPDR OR (95% CI) PDR OR (95% CI) P trend
Model 1*
    Cholesterol (1.3), mmol/L 1.00 (0.63–1.59) 0.77 (0.60–0.99) 1.18 (0.79–1.77) 0.86 (0.67–1.10) 0.26
    Triglyceride (1.0), mmol/L 1.49 (0.97–2.45) 1.00 (0.75–1.34) 1.09 (0.71–1.67) 1.07 (0.81–1.41) 0.72
    HDL-C (1.1), mmol/L 1.02 (0.66–1.58) 0.88 (0.69–1.13) 0.86 (0.51–1.43) 0.93 (0.72–1.20) 0.36
    Non HDL-C (1.3), mmol/L 0.99 (0.62–1.59) 0.80 (0.62–1.03) 1.23 (0.83–1.84) 0.87 (0.68–1.12) 0.39
    LDL-C (1.3), mmol/L 0.77 (0.46–1.31) 0.77 (0.60–0.98) 1.18 (0.79–1.76) 0.88 (0.69–1.12) 0.38
    LDL-C/HDL-C (1.2) 0.82 (0.45–1.47) 0.73 (0.54–0.98) 1.11 (0.78–1.58) 0.88 (0.67–1.16) 0.41
    Chol/HDL-C (1.2) 0.88 (0.51–1.52) 0.80 (0.61–1.05) 1.26 (0.84–1.88) 0.99 (0.76–1.27) 0.89
Model 2†
    Cholesterol (1.3), mmol/L 1.02 (0.60–1.74) 0.73 (0.53–1.01) 1.16 (0.72–1.86) 0.79 (0.57–1.11) 0.20
    Triglyceride (1.0), mmol/L 1.55 (0.97–2.47) 1.02 (0.71–1.48) 1.12 (0.69–1.83) 1.16 (0.81–1.66) 0.48
    HDL-C (1.1), mmol/L 0.97 (0.61–1.56) 0.89 (0.67–1.19) 0.90 (0.51–1.56) 0.90 (0.66–1.24) 0.34
    Non HDL-C (1.3), mmol/L 1.05 (0.61–1.80) 0.76 (0.55–1.05) 1.22 (0.76–1.96) 0.83 (0.59–1.16) 0.33
    LDL-C (1.3), mmol/L 0.75 (0.41–1.36) 0.69 (0.50–0.95) 1.06 (0.67–1.70) 0.76 (0.55–1.06) 0.14
    LDL-C/HDL-C (1.2) 0.86 (0.48–1.55) 0.66 (0.46–0.96) 1.09 (0.69–1.75) 0.85 (0.59–1.21) 0.41
    Chol/HDL-C (1.2) 0.93 (0.51–1.70) 0.74 (0.53–1.04) 1.30 (0.81–2.07) 1.03 (0.74–1.43) 0.64
Table 3.
 
Association of Serum Lipids with the Severity of DME
Table 3.
 
Association of Serum Lipids with the Severity of DME
Serum Lipids (Per SD Increase) Mild DME OR (95% CI) Moderate DME OR (95% CI) CSME OR (95% CI) P trend
Model 1*
    Cholesterol (1.3), mmol/L 0.90 (0.63–1.29) 0.81 (0.54–1.19) 1.41 (1.09–1.82) 0.08
    Triglyceride (1.0), mmol/L 0.92 (0.62–1.37) 0.79 (0.49–1.29) 1.11 (0.86–1.43) 0.72
    HDL-C (1.1), mmol/L 1.02 (0.70–1.50) 0.96 (0.64–1.42) 1.04 (0.78–1.38) 0.94
    Non HDL-C (1.3), mmol/L 0.89 (0.61–1.29) 0.81 (0.55–1.21) 1.40 (1.10–1.81) 0.07
    LDL-C (1.3), mmol/L 0.89 (0.61–1.29) 0.85 (0.58–1.26) 1.50 (1.17–1.93) 0.02
    LDL-C/HDL-C (1.2) 0.96 (0.64–1.46) 0.75 (0.46–1.22) 1.34 (1.04–1.71) 0.06
    Chol/HDL-C (1.2) 0.96 (0.66–1.39) 0.76 (0.49–1.18) 1.41 (1.08–1.84) 0.08
Model 2†
    Cholesterol (1.3), mmol/L 0.74 (0.45–1.09) 0.84 (0.52–1.18) 1.50 (1.08–1.96) 0.07
    Triglyceride (1.0), mmol/L 0.96 (0.59–1.48) 0.78 (0.48–1.25) 1.00 (0.74–1.36) 0.77
    HDL-C (1.1), mmol/L 0.79 (0.49–1.27) 0.88 (0.57–1.37) 1.18 (0.86–1.62) 0.60
    Non HDL-C (1.3), mmol/L 0.77 (0.46–1.14) 0.79 (0.51–1.21) 1.41 (1.04–1.90) 0.10
    LDL-C (1.3), mmol/L 0.69 (0.45–1.09) 0.83 (0.55–1.25) 1.55 (1.15–2.09) 0.06
    LDL-C/HDL-C (1.2) 0.88 (0.54–1.45) 0.74 (0.44–1.26) 1.37 (1.06–1.77) 0.05
    Chol/HDL-C (1.2) 0.94 (0.61–1.46) 0.75 (0.46–1.22) 1.43 (1.04–1.97) 0.10
Table 4.
 
Association of Serum Lipids with CSME
Table 4.
 
Association of Serum Lipids with CSME
Serum Lipids At Risk (n) Model 1 OR (95% CI) P Model 2 OR (95% CI) P
Cholesterol, mmol/L
    1st quintile, ≤3.5 97 1.00 1.00
    2nd quintile, 3.6–4.2 95 1.41 (0.53–3.73) 1.06 (0.38–3.30)
    3rd quintile, 4.3–4.7 100 1.21 (0.45–3.24) 1.36 (0.46–3.96)
    4th quintile, 4.8–5.6 92 2.56 (1.02–6.40) 4.34 (1.57–12.0)
    5th quintile, ≥5.7 83 2.88 (1.12–7.12) 0.006* 3.48 (1.26–9.64) 0.001*
    Per SD (1.3) increase 1.45 (1.13–1.86) 0.003 1.54 (1.15–2.07) 0.003
Triglyceride, mmol/L
    1st quintile, ≤1.0 110 1.00 1.00
    2nd quintile, 1.1–1.4 95 1.38 (0.55–3.47) 1.28 (0.45–3.64)
    3rd quintile, 1.5–1.8 85 2.78 (1.19–6.52) 2.60 (1.00–6.74)
    4th quintile, 1.9–2.5 92 1.66 (0.68–4.05) 1.72 (0.64–4.61)
    5th quintile, ≥2.6 84 1.72 (0.70–4.20) 0.21* 1.47 (0.53–4.08) 0.37*
    Per SD (1.1) increase 1.14 (0.89–1.47) 0.30 1.04 (0.78–1.40) 0.74
HDL-C, mmol/L
    1st quintile, ≤1.0 100 1.00 1.00
    2nd quintile, 1.1–1.2 101 1.11 (0.49–2.51) 1.11 (0.44–2.81)
    3rd quintile, 1.3–1.4 85 1.28 (0.55–3.01) 1.46 (0.56–3.76)
    4th quintile, 1.5–1.7 94 1.37 (0.60–3.14) 1.29 (0.50–3.32)
    5th quintile, ≥1.8 84 0.94 (0.36–2.43) 0.84* 1.33 (0.46–3.84) 0.52*
    Per SD (1.0) increase 1.04 (0.79–1.38) 0.77 1.21 (0.89–1.65) 0.22
Non HDL-C, mmol/L
    1st quintile, ≤2.1 94 1.00 1.00
    2nd quintile, 2.2–2.7 94 2.82 (0.95–8.32) 1.74 (0.52–5.78)
    3rd quintile, 2.8–3.2 96 2.27 (0.75–6.85) 1.99 (0.63–6.26)
    4th quintile, 3.3–4.1 88 3.37 (1.14–9.92) 3.64 (1.18–11.2)
    5th quintile, ≥4.2 92 4.82 (1.72–13.5) 0.003* 4.95 (1.63–15.1) 0.001*
    Per SD (1.4) increase 1.45 (1.13–1.86) 0.003 1.49 (1.11–1.99) 0.007
LDL-C, mmol/L
    1st quintile, ≤1.6 97 1.00 1.00
    2nd quintile, 1.7–2.0 107 3.13 (0.98–9.96) 3.82 (1.14–12.8)
    3rd quintile, 2.1–2.4 77 3.18 (0.93–10.9) 2.32 (0.59–9.03)
    4th quintile, 2.5–3.2 83 4.29 (1.33–13.8) 5.38 (1.61–17.9)
    5th quintile, ≥3.3 86 6.63 (2.15–10.5) 0.001* 8.02 (2.42–26.5) <0.001*
    Per SD (1.4) increase 1.54 (1.21–1.98) 0.001 1.63 (1.22–2.19) <0.001
LDL-C/HDL-C
    1st quintile, ≤1.1 95 1.00 1.00
    2nd quintile, 1.2–1.5 92 1.49 (0.45–4.92) 1.20 (0.35–4.12)
    3rd quintile, 1.6–2.0 84 3.14 (1.07–9.24) 2.39 (0.74–7.72)
    4th quintile, 2.1–2.6 100 3.81 (1.32–10.9) 3.18 (1.04–9.78)
    5th quintile, ≥2.7 78 5.26 (1.82–15.2) <0.001* 4.89 (1.54–15.5) 0.001*
    Per SD (1.2) increase 1.37 (1.07–1.75) 0.014 1.41 (1.10–1.82) 0.008
Chol/HDL-C
    1st quintile, ≤2.5 97 1.00 1.00
    2nd quintile, 2.6–3.1 99 2.20 (0.71–6.75) 1.39 (0.42–4.66)
    3rd quintile, 3.2–3.8 86 3.95 (1.37–11.4) 3.08 (1.00–9.53)
    4th quintile, 3.9–4.7 91 2.83 (0.94–8.53) 2.47 (0.76–8.08)
    5th quintile, ≥4.8 92 5.59 (1.97–15.9) 0.001* 4.78 (1.51–15.1) 0.003*
    Per SD (1.2) increase 1.46 (1.13–1.89) 0.004 1.49 (1.09–2.03) 0.012
Table st1, DOC
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