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Retinal Nerve Fiber Layer (RNFL) Changes in Type 2 Diabetes taking Cholesterol Lowering Medications

INTRODUCTION Diabetes has been associated with diabetic neuropathy and now implicated in neurodegenerative disorders.1Glaucoma, according to recent studies, can be considered a neurodegenerative disease, with retinal ganglion cell (RGC) loss and characteristic optic nerve head changes and visual field defects.2, 3 The axons of RGC which compose the retinal nerve fiber layer (RNFL), is the most superficial layer of the ten layers of the retina and can be easily seen using ophthalmic imaging techniques.RNFL thinning is an early indicator of glaucomatous optic neuropathy and is also present in diabetes prior to the detection of diabetic retinopathy.4, 5Because axons within the RNFL are unmyelinated, RNFL thickness is an ideal quantifiable assessment of axonal neurodegeneration.6 Recent clinical trials suggest statins to be neuroprotective in a number of neurodegenerative diseases.Many Type 2 diabetic patients have hyperlipidemia and are treated with statins, selective inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Studies examining the protective effects of statins on various eye diseases such as age-related macular degeneration, cataract, glaucoma, and diabetic retinopathy yield mixed findings.8, 9 However, the role of statins in diabetic eye changes is not well documented. We postulate that statins may also have a neuroprotective effect in diabetic retinopathy. We propose to study its effect on RNFL thickness in Type 2 diabetic patients. METHODS Patients A retrospective case-controlled study of Type 2 diabetes mellitus (NIDDM) patients from a Retina-Vitreous clinic in San Jose, California was used to evaluate the effect of statins on retinal nerve fiber layer thickness. Eligibility criteria included patients ages 18 and older, and diagnosis of diabetes or pre-diabetes according to the 2010 criteria of the American Diabetes Association: diabetic HbA1c ≥ 6.5% or fasting plasma glucose (FPG) ≥ 126 mg/dL, pre-diabetic HbA1c 5.7-6.4% or FPG 100-125 mg/dL.10 All patients underwent a comprehensive ophthalmic examination, including a review of medical history and medication list, measurement of visual acuity (Snellen), intraocular pressure (applanation tonometry), slit-lamp examination, dilated funduscopic examination and photography (TRC 50-EX, Topcon Corp, Tokyo, Japan), and optical coherence tomography (OCT) of the macula and RNFL (Heidelberg Spectralis, Heidelberg, Germany). Laboratory lipid panels were required to be within 4 months of ophthalmic examination, and consisted of risk factors related to diabetes: total cholesterol, triglycerides, LDL, HDL, FPG, and HbA1c. Patients were included if they had best corrected visual acuity of 20/20 to 20/40. Diabetic patients were categorized into Plus-Statins or Neg-Statins groups based on the use or no use of statins, respectively. Non-diabetic patients with no statin use were included in the Control group. Exclusion criteria were patients with the diagnosis of glaucoma (based on visual field defect or intraocular pressure (IOP) > 22 mmHg), age-related macular degeneration, or history of retinal or glaucoma laser treatment. Optical Coherence Tomography Optical coherence tomography (OCT) is a real-time diagnostic imaging technique that uses low coherence interferometry of backscattered infrared light, 11 thereby producing high-resolution cross-sectional images of retinal structures and pathologies.11 Of interest, it measures RNFL thickness, a quantifiable indicator for early glaucoma. 11 Spectral-domain OCT (SD-OCT) is a recent imaging tool that provides scans over a larger retinal area, faster acquisition time, and higher resolution compared to the traditional time-domain OCT. 12 In the present study, SD-OCT imaging was performed using Spectralis HRA-OCT (Heidelberg Engineering, Heidelberg, Germany; software version 5.4.6). An “IR-OCT, Glaucoma, RNFL” scan protocol was used to measure the peripapillary RNFL, producing a circular B-scan (3.4 mm diameter, 768 A-scans), manually positioned at the optic disc center.13 RNFL thickness was measured and reported as an overall mean, by quadrants, and by clock hours. Figure 1 Figure 1. Example of RNFL thickness map and corresponding average and quadrant RNFL measurements of a patient from the control group, generated with the Heidelberg SD-OCT. Statistical Analysis All numerical data obtained from the study were entered in an Excel spreadsheet (Microsoft, Seattle, WA) for statistical analysis. Patient age, duration of diabetes, and lipid profiles were summarized using means and standard deviations; comparisons were done using student paired t-tests. Categorical data (race and gender) were summarized using frequencies and percentages. The average (Avg), superior (Sup), temporal (Tmp), inferior (Inf) and nasal (Nas) RNFL regions were compared between Control, Plus-Statins and Neg-Statins groups using student paired t-tests. The sample size required for a two-tailed paired t-test of 80% power was 24 patients. Statistical significance was set at P < 0.05. RESULTS Sixty six diabetic patient charts met the inclusion criteria: 36 patients taking cholesterol medication (Plus-Statins) and 30 patients not taking cholesterol medication (Neg-Statins). Patients from Plus-Statins and Neg-Statins groups were divided into subgroups of ages 40-49 and 60-79 years. For age-matching, fifteen patients were randomly selected from each subgroup using a coin toss. A total of 60 diabetic patients were included in the analysis: 30 patients in Plus-Statins and 30 patients in Neg-Statins. In the Plus-Statins group, there were 18 males and 12 females (average age58.2 years, SD 8.5 years). In the Neg-Statins group, there were 19 males and 11 females (average age 57.3 and SD 9.9 years). Demographics (age, gender, race), and duration of diabetes are summarized in Table 1. Lipid profile parameters between Plus-Statins and Neg-Statins groups are compared using student paired t-tests in Table 2. There were no significant differences in age, total cholesterol, triglycerides, HDL, and FPG levels. The significant difference found in LDL levels confirmed the use and effect of statins in those patients who were taking cholesterol medications. An additional 30 non-diabetic patients were included in the Control group for comparison. Demographic and lipid profile comparison of p-values between Control, Plus-Statins and Neg-Statins groups are summarized in Table 3. Table 1. Demographics and lipid profiles of Plus-Statins, Neg-Statins and Control groups.

Plus-Statins n=30

Neg-Statins

n=30

Control n=30

Age (yrs)Mean ± SD Range

58.2 ± 8.5

37-75

57.3 ± 9.9

39-79

56.3 ± 9.9

39-75

DM Duration (yrs)Mean ± SD Range

6.4 ± 4.6

1-20

5.1 ± 5.6

1-20

Gender, n (%)Male Female

18 (60.0)

12 (40.0)

19 (63.3)

11 (36.7)

8 (26.6)

22 (73.3)

Race, n (%)African

2 (6.7)

2 (6.7)

0 (0)

Asian

14 (46.7)

17 (56.7)

16 (53.3)

Caucasian

11 (36.7)

9 (30.0)

12 (40.0)

Hispanic

3 (10.0)

2 (6.7)

2 (6.6)

Lipid Profile, mean ± SD (range)
HbA1c (%)

7.0 ± 1.6 (5.8-14.1)

6.9 ± 2.2 (5.7-16.5)

5.4 ± 0.1 (5.3-5.6)

FPG (mg/dL)

119.5 ± 21.0 (69-152)

112.3 ± 33.5 (77-241)

82.3 ± 6.5 (72-95)

Total Chol (mg/dL)

159.6 ± 30.0 (119-237)

183.6 ± 48.1 (115-280)

205.5 ± 35.0 (158-261)

TG (mg/dL)

123.3 ± 64.8 (54-293)

143.5 ± 68.4 (61-320)

101.9 ± 56.9 (53-251)

HDL (mg/dL)

54.7 ± 13.9 (30-78)

53.5 ± 20.8 (29-108)

68.7 ± 21.3 (35-109)

LDL (mg/dL)

78.5 ± 28.5 (41-153)

101.5 ± 33.5 (48-200)

116.6 ± 26.5 (79-153)

DM= diabetes mellitus, FPG = fasting plasma glucose, TG = triglycerides, HDL = high density lipoprotein, LDL = low density lipoprotein

Table 2. Age and lipid profile comparisons between Plus-Statins vs. Neg-Statins, Control vs. Plus-Statins and Control vs. Neg-Statins groups using student paired t-tests.

Plus-Statins vs. Neg-Statins p-value

Control vs. Plus-Statins

p-value

Control vs. Neg-Statins

p-value

Age (yrs)

0.94

0.27

0.46

DM Duration (yrs)

0.40

HbA1c (%)

0.86

0.001

0.08

FPG (mg/dL)

0.44

0.001

0.12

Total Chol (mg/dL)

0.06

0.05

0.13

TG (mg/dL)

0.28

0.0003

0.10

HDL (mg/dL)

0.81

0.08

0.28

LDL (mg/dL)

0.03

0.05

0.16

Mean values of the RNFL parameters in the three groups are shown in Table 3. RNFL thicknesses of Control, Plus-Statins and Neg-Statins groups are compared using student paired t-test in Table 4. Table 3. RNFL thicknesses (µm) for average, superior, temporal, inferior and nasal regions.

Plus-Statins (n=30) ± SD (range)

Neg-Statins (n=30) ± SD (range)

Control (n=30) ± SD (range)

RNFL Thickness OD
Avg RNFL (µm)

100.2 ± 10.2 (83-124)

90.7 ± 13.2 (55-117)

103.8 ± 8.7 (87-127)

Sup RNFL (µm)

116.4 ± 18.2 (68-147)

103.7 ±22.1 (33-139)

119.9 ± 17.8 (85-162)

Tmp RNFL (µm)

80.6 ± 15.8 (54-128)

77.6 ± 19.3 (46-125)

77.7 ± 12.4 (55-113)

Inf RNFL (µm)

129.2 ± 18.3 (93-164)

114.8 ± 19.0 (63-157)

134.4 ± 28.0 (12-180)

Nas RNFL (µm)

75.7 ±17.8 (44-140)

66.3 ± 16.0 (15-92)

79.9 ± 15.4 (57-119)

RNFL Thickness OS
Avg RNFL (µm)

99.2 ± 10.3 (81-116)

92.4 ± 11.5 (69-121)

105.2 ± 7.6 (92-126)

Sup RNFL (µm)

119.2 ±21.7 (50-164)

109.8 ± 18.0 (73-136)

124.9 ± 15.1 (99-160)

Tmp RNFL (µm)

76.6 ± 15.9 (51-115)

73.9 ± 21.7 (44-148)

75.4 ± 13.2 (50-97)

Inf RNFL (µm)

127.8 ± 20.7 (67-171)

115.4 ± 16.6 (68-146)

132.2 ± 19.5 (81-177)

Nas RNFL (µm)

70.9 ± 18.1 (35-105)

69.0 ± 16.4 (39-101)

83.0 ± 19.5 (49-145)

Table 4.Student paired t-test comparison of RNFL thicknesses (µm).

Plus-Statins vs. Neg-Statins p-value

Control vs. Plus-Statins

p-value

Control vs. Neg-Statins

p-value

RNFL Thickness OD
Avg RNFL (µm)

0.002

0.18

0.000006

Sup RNFL (µm)

0.011

0.57

0.004

Tmp RNFL (µm)

0.493

0.26

0.99

Inf RNFL (µm)

0.004

0.45

0.003

Nas RNFL (µm)

0.033

0.34

0.002

RNFL Thickness OS
Avg RNFL (µm)

0.013

0.01

0.00002

Sup RNFL (µm)

0.051

0.28

0.002

Tmp RNFL (µm)

0.636

0.88

0.68

Inf RNFL (µm)

0.012

0.27

0.0006

Nas RNFL (µm)

0.497

0.03

0.008

DISCUSSION In this study, retinal nerve fiber layer thickness is greater in diabetic patients taking statin medication compared with diabetic patients not taking statins. The average and superior, inferior and nasal quadrants show significantly thicker RNFL layers for the Plus-Statins group, while the temporal quadrant shows a trend for increased RNFL thickness. Generally, in diabetic eyes, significant RNFL thinning is correlated with duration of diabetes.14 However, we found that with the use of statins, duration of diabetes does not play a role in RNFL thinning. When compared with non-diabetic Controls, diabetic patients taking statins have no significant difference in RNFL thickness, suggesting that statins may reduce the rate of neurodegeneration caused by Type 2 diabetes. Several studies have shown that diabetes has an early neurodegenerative effect on the retina, although the pathophysiology for this is still unclear. 15-17 RNFL thinning is associated with decreased visual function, and is one of the clinical methods for diagnosing glaucoma. In fact, glaucomatous visual field loss is measurable when 40% of the retinal ganglion cells (RGC) which compose the RNFL have been lost.4 Neuronal apoptosis of RGC is induced by oxidative injury due to mitochondrial dysfunction; thus the related molecular pathway is a potential therapeutic target to protect against optic nerve damage in glaucoma.18, 19 Statins, which are selective inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA), have been found to be neuroprotective, potentially due to their upregulation of endothelial nitric oxide synthase (eNOS) leading to anti-inflammatory properties (Figure 2).6 If statins exhibit a neuroprotective effect for retinal neurons, then statins may play a role in slowing the progression of glaucoma in diabetic patients. Figure 2 Figure 2. Upregulation of endothelial nitric oxide synthase (eNOS) by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), resulting in increased nitric oxide (NO) synthesis and corresponding anti-inflammatory, anti-thrombotic, and vasodilation properties. The neuroprotective effect of statins has been researched in detail for neurodegenerative diseases such as Alzheimer’s and amyotrophic (ALS), as well as for prevention of stroke and brain hemorrhaging.20-22 Of interest, one retrospective longitudinal analysis found statins to be associated with reduced risk of open angle glaucoma (OAG) in persons with hyperlipidemia.23 Although little research has been done for the mechanism of action of statins within the eye, one study using db/db mice shows that statin treatment normalizes diabetic changes in expression of proinflammatory factors, increases vascular leakage, and decreases tight protein levels in the retina.22,19 Statins may also attenuate the inflammatory cytokine responses to ameliorate ischemic oxidative stress and prevent neurological damage. 22 However, there are currently limited studies on the adverse effects of statins on ocular structures. Although there is no elevated risk of cataract development in humans from taking statins, animal models have indicated a higher risk of cataract development through the rho-kinase inhibition by statins. 24, 25 Further investigation with long-term follow-up is needed to determine if there are adverse ocular side effects after long-term use. CONCLUSION This small study suggests that statins may be associated with preserving retinal nerve fiber layer thickness in diabetic patients. Because this is a retrospective case-controlled study, we did not look at patient compliance, duration of statin usage, or the type of statin used. Further controlled clinical trials with expanded patient recruitment are needed. In-vitro research may further elucidate possible mechanisms of action by these cholesterol-lowering agents on the retinal nerve fiber layer.

References

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