Hindawi

Journal of Ophthalmology
Volume 2020, Article ID 1875860, 6 pages
https://doi.org/10.1155/2020/1875860

Clinical Study
Systemic Factors Associated with Treatment Response in Diabetic
Macular Edema

Wendy Meihua Wong ,1 Caroline Chee,1 Mayuri Bhargava,1 Charmaine Chai,1 Hazel Lin,1
Paul Zhao,1 Erlangga Ariadarma Mangunkusumo,1 Thet Naing,1 Yew Sen Yuen,1
Tien Yin Wong,1,2 Xinyi Su ,1,2,3,4 and Gopal Lingam 1,3
1
National University Hospital, Singapore
2
Singapore Eye Research Institute, Singapore
3
National University of Singapore, Singapore
4
Institute of Molecular and Cell Biology, A∗STAR, Singapore

Correspondence should be addressed to Xinyi Su; xinyi_su@nuhs.edu.sg and Gopal Lingam; lingamgopal@gmail.com

Received 19 August 2019; Revised 15 February 2020; Accepted 26 February 2020; Published 23 March 2020

Guest Editor: Ali Dirani

Copyright © 2020 Wendy Meihua Wong et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Purpose. To identify systemic factors that may influence the response to anti-VEGF therapy in patients with diabetic macular
edema (DME). Methods. 35 patients undergoing anti-VEGF injections for centre-involving DME were studied in this prospective
observational study. The primary outcome was change in macular thickness one month after treatment, measured using spectral-
domain optical coherence tomography (OCT). At baseline, information on various systemic factors was collected including
glycosylated hemoglobin (HbA1c), serum VEGF levels, lipid profile and markers of renal function, and blood pressure. Thirty-
three of the 35 patients were included in this study. Nonparametric statistical tests were used for the analysis of the data in view of
the nonnormal distribution of the outcome variables. Multivariate analysis was performed using logistic regression. Stata 12.1
software was used for the analysis. Main Outcome Measures. Reduction in macular central subfield thickness (on spectral-domain
OCT) and change in logMAR visual acuity at one month after injection. Results. Lower HbA1c levels (7% or less) were significantly
associated with greater reduction in central macular subfield thickness at one month after injection of bevacizumab or rani-
bizumab on both univariate analysis (p � 0.012) and multivariate analysis (p � 0.042). Conclusions. Better glycemic control is
associated with a greater reduction in central macular thickness after the first injection of bevacizumab or ranibizumab in diabetic
macular edema. Patients with high levels of HbA1c and poor response to anti-VEGF may benefit from strict control of their
blood glucose.

1. Introduction patients with DME, causing visual impairment. Several

landmark studies have demonstrated that anti-VEGF
Diabetic macular edema (DME) is a vision-threatening therapy, compared to laser photocoagulation, provides su-
complication of diabetes. In DME, accumulation of fluid in perior visual outcomes [3, 4]. In the Diabetic Retinopathy
the macula results in loss of central vision, which is im- Clinical Research Network Protocol T, three commonly used
portant for facial recognition, reading, and driving. DME anti-VEGF agents, bevacizumab, ranibizumab, and afli-
affects 1 in 15 people with diabetes [1] and is the leading bercept, were shown in the randomized controlled trial to
cause of blindness in young adults in developed countries improve vision in centre-involving DME [5].
[2]. Despite the proven benefits of anti-VEGF therapy, a
Intravitreal injections of antivascular endothelial growth subgroup of patients has persistent DME after an initial
factor (anti-VEGF) have revolutionized the treatment of course of anti-VEGF therapy. A secondary analysis of
2 Journal of Ophthalmology

Protocol T showed that after six monthly intravitreal anti- and CST, between baseline and one month after IVT anti-
VEGF injections, persistent macular thickening was present VEGF, was used to assess the functional and morphological
in 65.6%, 41.5%, and 31.6% of eyes treated with bev- response to treatment, respectively. Study participants re-
acizumab, ranibizumab, and aflibercept, respectively [6]. The ceived either intravitreal bevacizumab (1.25 mg in 0.05 ml)
clinical challenge of predicting individual response to anti- or ranibizumab (0.5 mg in 0.05 ml).
VEGF therapy remains. Being able to do so will be invaluable
for the physician to counsel patients and manage
2.4. Statistical Analysis. The Snellen BCVA was converted to
expectations.
LogMAR units and the ETDRS letter score for statistical
The influence of systemic factors on the occurrence of
analysis.
diabetic retinopathy and other micro- and macrovascular
Continuous variables were dichotomised as normal and
complications has been well studied. Studies have shown
abnormal. The value for dichotomisation was based on
that tight control of blood sugar and other associated sys-
published literature (>140 mmHg for systolic BP [12];
temic factors such as hypertension, serum cholesterol, and
>90 mm/hg for diastolic blood pressure [5]; >7.0% for
kidney function can significantly delay the onset of diabetic
HbA1c [13]; and >308 pg/mL for serum VEGF levels [14]) or
retinopathy [7–11]. However, it is not known if these sys-
the laboratory-specific reference range (>5.2 mmol/litre for
temic factors affect the anatomical and visual response to
cholesterol; >2.2 mmol/litre for triglycerides; >3.3 mmol/
anti-VEGF intravitreal injections.
litre for LDL; <1 mmol/litre for HDL; >3.5 for total cho-
In this prospective study, we explored whether systemic
lesterol : HDL ratio; >120 μmol/litre for serum creatinine;
factors, such as blood pressure, glucose control, cholesterol,
and <90 ml/min/1.73 m2 for eGFR).
triglyceride, and creatinine levels at the time of intravitreal
anti-VEGF injection, affect the visual or anatomic response Univariate analysis was performed with nonparametric
at one month after initiating the treatment. tests as the distribution of the outcome variables were
significantly skewed to the right. Evaluation of the effect of
each of the systemic factors (normal vs abnormal) on the
2. Materials and Methods change in CST and BCVA was performed with Man-
2.1. Study Design. This prospective, single-centre, observa- n–Whitney U test. Spearman correlation test was performed
tional study was conducted with Institutional Review Board for testing correlation between linear variables such as visual
approval and adhered to the tenets of the Declaration of acuity and central subfield thickness. Multivariate analysis
Helsinki. Informed consent was obtained from all study was performed using logistic regression analysis and step-
participants. Eligible participants had centre-involved DME wise backward selection of variables to be included in the
confirmed on spectral-domain optical coherence tomogra- final model. The Strata 12.1 software was used for statistical
phy (OCT) (Spectralis HRA + OCT, Heidelberg Engineer- analysis.
ing, Heidelberg, Germany). Patients who had prior
vitreoretinal surgery, laser, or anti-VEGF injections to the 3. Results
study eye within 2 months or were unable to come for review
one month after the injection were excluded. The study 3.1. Baseline Characteristics. Over a one-year period, 35 eyes
recruited consecutive patients who required anti-VEGF for of 35 participants received either intravitreal bevacizumab
treatment of DME and were able to provide informed (n � 25, 71.4% of eyes) or ranibizumab (n � 10, 28.6% of
consent. eyes). Data were analyzed for 33 eyes that completed the
one-month follow-up visit.
The baseline demographic and study eye characteristics
2.2. Assessment of Systemic and Metabolic Parameters. are summarized in Table 1. The mean duration of diabetes
The following baseline clinical characteristics were recorded: for study participants was 11.8 ± 9.5 years. The mean
age; gender; duration of diabetes; diabetic medications; and baseline CST was 440.5 ± 136.3 microns. There was no sta-
associated systemic conditions such as hypertension, ne- tistically significant difference in the mean baseline CST of
phropathy, and ischemic heart disease. patients with HbA1c ≤7.0% and patients with HbA1c >7.0%
On the day of injection, blood was collected to check the (p � 0.27).
glycosylated hemoglobin (HbA1c) and serum VEGF levels, The systemic and metabolic factors at time of anti-VEGF
lipid profile (triglyceride, total cholesterol, and fractions), treatment are shown in Table 2. The serum HbA1c was
and markers of renal function (estimated glomerular fil- greater than 7.0% in 57.1% of participants.
tration rate (eGFR) and serum creatinine). The brachial No correlation was found between the baseline CST and
systolic and diastolic blood pressures (BP) were recorded BCVA (Spearman correlation test).
twice with a digital manometer, at intervals of 10 minutes,
with the lower of the two recordings taken as the final value.
3.2. Effect of Treatment on Visual Acuity. The final visual
acuity was 6/12 (70 letters) or better in 51.4%; >6/60 to <6/12
2.3. Assessment and Treatment of DME. The Snellen best (36 to 69 letters) in 34.3%; and less than or equal to 6/60 (35
corrected visual acuity (BCVA) was recorded. The central letters) in 8.6%. The visual acuity was unchanged in 12 eyes
subfield thickness (CST) was measured on spectral-domain (36.4%). The visual acuity improved in 11 eyes (33.3%), with
optical coherence tomography (OCT). The change in BCVA an increase in the visual-acuity letter score ranging from 3 to
Journal of Ophthalmology 3

Table 1: Patient demographics, clinical, and ocular characteristics (n � 35).

Parameter Number (percentage)
Male 17 (48.6)
Gender
Female 18 (51.4)
Demographics
Mean/SD62.1 yrs/SD-7.4
Age
Range 50–80 yrs
Oral hypoglycemic agents 20 (57.14)
Treatment for diabetes mellitus Only insulin 4 (11.4)
Insulin + oral hypoglycemic agents 11 (31.4)
Hypertension 34 (97.1)
Ischemic heart disease 11 (31.4)
Comorbidities
Nephropathy 17 (48.6)
On renal dialysis 3 (8.6)
6/12 or better 21 (60)
Snellen best corrected visual acuity >6/60 to <6/12 11 (34)
≤6/60 3 (8.6)
Ocular features Minimal cataract 19 (54.3)
Lens status Significant cataract 8 (22.9)
Pseudophakia 8 (22.9)
Proliferative diabetic retinopathy 2 (5.7)
PRP 18 (51.4)
Previous laser Macular 6 (17.1)
Prior treatment for diabetic retinopathy/maculopathy
Both 2 (5.7)
Prior intravitreal anti-VEGF therapy 23 (65.7)
SD, standard deviation; PRP, pan retinal photocoagulation; anti-VEGF, antivascular endothelial growth factor.

Table 2: Prevalence of abnormal parameters related to systemic 3.4. Association of Systemic Factors with Anatomical and
condition (n � 35). Visual Response. Tables 3 and 4 summarize the results of
S/N Parameter Number (percentage) univariate and multivariate analysis of influence of various
1 Systolic blood pressure >140 mm/hg 23 (65.7)
independent variables on the outcome variables.
2 Diastolic blood pressure >90 mm/hg 4 (11.4) On univariate analysis, only the HbA1c level was sig-
3 Serum creatinine >120 μmol/litre 16 (45.7) nificantly associated with reduction of CST after anti-VEGF
4 eGFR <90 ml/min/1.73 m2 25 (71.4) treatment (p � 0.012). The mean reduction in CST was
5 Serum total cholesterol >5.2 mmol/L 10 (28.6) 130 μm in the group with HbA1c ≤7.0% and 41.9 μm in the
6 Serum triglycerides >2.2 mmol/L 13 (37.1) group with HbA1c >7.0%. On multivariate logistic regres-
Serum high density lipoproteins sion analysis, the HbA1c level was associated with reduction
7 6 (17.1)
<1 mmol/L in CST after anti-VEGF therapy (odds ratio −0.019, 95%
Serum low-density lipoproteins confidence interval 0.042 to 0.944). The serum levels of
8 9 (25.7)
>3.3 mmol/L VEGF had a moderate correlation with the reduction of
9 Ratio of LDL to total cholesterol >3.5 21 (60)
CST, but this difference did not achieve statistical signifi-
10 Serum HbA1c >7% 20 (57.1)
11 Serum VEGF levels >308 pg/mL 24 (68.6)
cance (p � 0.1894).
The change in BCVA after treatment did not have any
eGFR, estimated glomerular filtration rate; LDL, low-density lipoproteins;
HbA1c, glycosylated hemoglobin; VEGF, vascular endothelial growth correlation with the systemic factors that were tested.
factor.
4. Discussion
35 letters. An improvement of ≥15 letters was observed in 2 In the management of diabetic macular edema, following
eyes (18.2%). The visual acuity worsened in 10 (30.3%) eyes, several landmark trials [3, 12, 13], anti-VEGF therapy has
with 3 eyes (30%) having a ≥15 letters decline in the visual- become the standard of care. However, a subgroup of pa-
acuity letter score. tients lacks “good” visual or anatomical response for unclear
reasons. Postulated factors include local factors, such as poor
retinal pigment epithelium health. In this study, we hy-
3.3. Effect of Treatment on Retinal Thickening. At 4 weeks pothesized that systemic factors have an important role in
after injection, the CST decreased, on average by the clinical response to anti-VEGF treatment.
82.03 ± 150.19 microns (range: −519 μm to + 138 μm). By
percentage (with reference to baseline) the change ranged
from −65.6% to +28.9%. The Spearman correlation test did 4.1. Association of Systemic Factors with Anatomical Response
not reveal any correlation between the change in the level of after Treatment. Our study has identified that HbA1c levels of
vision and the change in CST. 7% or less, at the time of intravitreal anti-VEGF injection, is
4 Journal of Ophthalmology

Table 3: Association of various systemic factors with change in central subfield thickness (CST) and change in logMAR visual acuity
(N � 33), (Mann–Whitney U test).
Change in
Reduction in CST logMAR visual
S/N Systemic factor p value acuity p value
Mean SD Mean SD
No (n � 23) 98.43 165.38 0.013 0.239
1 IHD 0.3371 0.7479
Yes (n � 10) 44.3 105.23 0.006 0.193
No (n � 30) 77.63 145.77 0.006 0.234
2 On dialysis 0.7542 0.2105
Yes (n � 3) 126 222.7 0.06 0.053
≤140 (n � 11) 71.73 180.23 −3.05 0.29
3 Systolic BP 0.4337 0.09532
>140 (n � 22) 87.18 137.18 0.016 0.192
≤90 (n � 29) 79.31 155.30 0.283 0.228
4 Diastolic BP 0.6994 0.1492
<90 (n � 4) 101.75 122.09 −0.115 0.160
≤120 (18) 77.61 134.9 −0.008 0.212
5 Creatinine 0.6255 0.2582
<120 (n � 15) 87.3 171.47 0.033 0.243
>90 (n � 8) 82.13 172.0 0.058 0.267
6 eGFR 0.8831 0.7961
<90 (n � 25) 82 146.44 −0.004 0.212
≤5.2 (n � 24) 72.67 147.39 −0.018 0.197
6 Total cholesterol 0.7464 0.2905
>5.2 (n � 9) 107.25 163.7 0.087 0.283
</ � 2.2 (n � 22) 91.14 166.77 0.054 0.244
7 Triglycerides 0.9239 0.1645
>2.2 (n � 11) 63.82 114.99 −0.075 0.153
≥1 (n � 27) 69.67 134.7 0.002 0.208
8 HDL cholesterol 0.7794 0.6322
<1 (n � 6) 137.67 213.2 0.05 0.307
</ � 3.3 (n � 25) 69.76 145.02 −0.017 0.192
9 LDL cholesterol 0.5015 0.2627
>3.3 (n � 8) 120.38 169.67 0.098 0.301
≤3.5 (n � 14) 41.86 75.49 −0.054 0.157
10 LDL: total cholesterol 0.8841 0.5558
>3.5 (n � 19) 111.63 183.86 0.059 0.256
≤7 (n � 15) 130.13 158.44 0.001 0.259
11 HbA1c 0.012 0.8821′
>7 (n � 18) 41.94 134.32 0.019 0.197
≤308 (n � 10) 41.1 132.49 0.008 0.065
12 Serum VEGF 0.1894 0.6879
>308 (n � 23) 99.83 156.64 0.012 0.267
CST, central subfield thickness; IHD, ischemic heart disease; BP, blood pressure; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein;
LDL, low-density lipoproteins; HbA1c, glycosylated hemoglobin; VEGF, vascular endothelial growth factor.

Table 4: Multivariate logistic regression analysis using stepwise In this study, the serum creatinine and glomerular filtration
backward selection for influence of various factors on reduction in rate (eGFR) did not show an association with CST after anti-
central macular thickness with anti-VEGF injection. VEGF therapy. Additionally, patients on dialysis did not
Confidence show a preferential lack of response to treatment, although
S/N Parameter Odds ratio p value interval our study may not be sufficiently powered to address this.
Lower Upper
1 HbA1c 0.019 0.042 0.042 0.944
2 LDL: total cholesterol 3.19 0.172 0.603 16.83
4.2. Association of Systemic Factors with Visual Outcome after
Treatment. Our study showed a significant association be-
Other factors were dropped during the stepwise backward selection.
tween lower HbA1c and CST reduction, but a similar as-
sociation was not found for BCVA. However, changes in the
associated with a better anatomical response, as assessed by the CST and the visual acuity do not necessarily correlate. In the
reduction in CST on OCT. This suggests that tight glucose DRCR.net Protocol I, the CST and VA of eyes treated with
control during the treatment period is important for good laser had a modest correlation [17]. In the DRCR.net Pro-
clinical outcome and is consistent with previous studies [14, 15]. tocol T, the change in CST at 12 weeks and visual acuity at 2
We also hypothesized that serum VEGF levels might years did not have a strong association [18].
reflect intraocular VEGF levels and thus predict the ana- There is conflicting evidence on correlation of HbA1c
tomical response to intravitreal anti-VEGF injections. Al- and visual response to anti-VEGF from large phase 3 trials
though a statistically significant difference was not found [19, 20]. An analysis of ranibizumab-treated patients from
(p � 0.1894), our results suggest a trend towards better the RISE and RIDE trials did not find an association between
anatomical response with lower serum VEGF levels. mean change in BCVA at weeks 52 and 100, with the
An earlier study found serum creatinine and cholesterol baseline HbA1c [19]. This is in contrast to an analysis of
levels to correlate with reduction in CST after treatment [16]. aflibercept-treated patients from the VISTA and VIVID
Journal of Ophthalmology 5

trials, which found that the mean improvement in VA at 2 Acknowledgments

years was dependent on HbA1c levels [21]. More recently, an
exploratory analysis of DRCR.net Protocol T, in which This study was supported by a grant from Singapore Eye
participants were randomized to receive bevacizumab, Research Institute (R1034/49/2013).
ranibizumab, or aflibercept, similarly found the magnitude
of vision improvement after anti-VEGF treatment to be References
associated with HbA1c levels [20].
One possible explanation for the discrepancy between [1] J. W. Yau, S. L. Rogers, R. Kawasaki et al., “Global prevalence
studies is that patients with similar HbA1c levels can have and major risk factors of diabetic retinopathy,” Diabetes Care,
marked differences in their daily glucose profiles, with vol. 35, no. 3, pp. 556–564, 2012.
variable frequency and duration of glucose excursions [2] P. Romero-Aroca, “Managing diabetic macular edema: the
[22, 23]. Transient hyperglycemic spikes can be a HbA1c- leading cause of diabetes blindness,” World Journal of Dia-
independent risk factor for diabetes-related complications, betes, vol. 2, no. 6, pp. 98–104, 2011.
[3] Q. D. Nguyen, D. M. Brown, D. M. Marcus et al., “Ranibi-
due to transient episodes of oxidative stress [24]. Most
zumab for diabetic macular edema: results from 2 phase III
studies have used HbA1c levels measured at the time of randomized trials: RISE and RIDE,” Ophthalmology, vol. 119,
injection which reflects the blood glucose control in the no. 4, pp. 789–801, 2012.
previous 2 months and not prospectively after administering [4] M. J. Elman, L. P. Aiello, R. W. Beck et al., “Randomized trial
treatment. This could also be a limitation in understanding evaluating ranibizumab plus prompt or deferred laser or
the correlation between HbA1c levels and response to anti- triamcinolone plus prompt laser for diabetic macular edema,”
VEGF treatment. Ophthalmology, vol. 117, no. 6, pp. 1064–1077, 2010.
[5] J. A. Wells, A. R. Glassman, A. R. Ayala et al., “Aflibercept,
bevacizumab, or ranibizumab for diabetic macular edema:
4.3. Study Strengths and Limitations. The principal strength two-year results from a comparative effectiveness randomized
of this study is the prospective evaluation of the impact of clinical trial,” Ophthalmology, vol. 123, no. 6, pp. 1351–1359,
other comorbidities on the short-term anatomical or visual 2016.
response to anti-VEGF treatment. There are several limi- [6] N. M. Bressler, W. T. Beaulieu, A. R. Glassman et al., “Per-
tations to this study, including the small sample size and sistent macular thickening following intravitreous aflibercept,
inclusion of study participants receiving different anti- bevacizumab, or ranibizumab for central-involved diabetic
VEGF agents. macular edema with vision impairment: a secondary analysis
of a randomized clinical trial,” JAMA Ophthalmology, vol. 136,
no. 3, pp. 257–269, 2018.
5. Conclusion [7] The Diabetes Control and Complications Trial Research
Group, “The relationship of glycemic exposure (HbA1c) to the
Although HbA1c has been demonstrated to be a marker and risk of development and progression of retinopathy in the
strong predictor of vascular complications in diabetic pa- diabetes control and complications trial,” Diabetes, vol. 44,
tients [7], its prognostic significance during treatment of no. 8, pp. 968–983, 1995.
DME and its effect on the efficacy is not clear. In our study, [8] UK Prospective Diabetes Study (UKPDS) Group, “Intensive
we identified that good glycemic control, as defined by an blood-glucose control with sulphonylureas or insulin com-
HbA1c level of less than 7%, in the period preceding anti- pared with conventional treatment and risk of complications
VEGF treatment, is associated with greater reduction in in patients with type 2 diabetes (UKPDS 33),” The Lancet,
central subfield thickness on macular OCT. This has sig- vol. 352, no. 9131, pp. 837–853, 1998.
[9] UK Prospective Diabetes Study Group, “Tight blood pressure
nificant implications for our clinical management of DME
control and risk of macrovascular and microvascular com-
patients with suboptimal response to initial anti-VEGF
plications in type 2 diabetes: UKPDS 38,” BMJ, vol. 317,
therapy. If the HbA1c levels are high in these patients, one no. 7160, pp. 703–713, 1998.
can enforce rigid control of blood glucose, continue with the [10] Diabetes Control and Complications Trial/Epidemiology Of
same therapy, and reassess, rather than switch to a different Diabetes Interventions and Complications Research Group,
drug. This is because the initial lack of optimal response J. M. Lachin, S. Genuth et al., “Retinopathy and nephropathy
might be due to the lack of proper blood glucose control. in patients with type 1 diabetes four years after a trial of
Our results also will help with patient counselling and intensive insulin therapy,” New England Journal of Medicine,
management of their expectations after their first intravitreal vol. 342, no. 6, pp. 381–389, 2000.
anti-VEGF injection. [11] T. Y. Wong, C. M. G. Cheung, M. Larsen, S. Sharma, and
R. Simó, “Diabetic retinopathy,” Nature Reviews Disease
Primers, vol. 2, no. 1, p. 16012, 2016.
Data Availability [12] J.-F. Korobelnik, D. V. Do, U. Schmidt-Erfurth et al.,
“Intravitreal aflibercept for diabetic macular edema,” Oph-
The data used to support the findings of this study are
thalmology, vol. 121, no. 11, pp. 2247–2254, 2014.
available from the corresponding author upon request. [13] M. Michaelides, A. Kaines, R. D. Hamilton et al., “A pro-
spective randomized trial of intravitreal bevacizumab or laser
Conflicts of Interest therapy in the management of diabetic macular edema (BOLT
study) 12-month data: report 2,” Ophthalmology, vol. 117,
The authors declare that they have no conflicts of interest. no. 6, pp. 1078–1086, 2010.
6 Journal of Ophthalmology

[14] B. T. Ozturk, H. Kerimoglu, M. Adam, K. Gunduz, and

S. Okudan, “Glucose regulation influences treatment outcome
in ranibizumab treatment for diabetic macular edema,”
Journal of Diabetes and its Complications, vol. 25, no. 5,
pp. 298–302, 2011.
[15] S. Matsuda, T. Tam, R. P. Singh et al., “The impact of met-
abolic parameters on clinical response to VEGF inhibitors for
diabetic macular edema,” Journal of Diabetes and Its Com-
plications, vol. 28, no. 2, pp. 166–170, 2014.
[16] F. A. Warid Al-Laftah, M. Elshafie, M. Alhashimi, A. Pai, and
M. Farouq, “Pretreatment clinical variables associated with
the response to intravitreal bevacizumab (Avastin) injection
in patients with persistent diabetic macular edema,” Saudi
Journal of Ophthalmology, vol. 24, no. 4, pp. 133–138, 2010.
[17] D. J. Browning, D. J. Browning, A. R. Glassman et al., “Re-
lationship between optical coherence tomography-measured
central retinal thickness and visual acuity in diabetic macular
edema,” Ophthalmology, vol. 114, no. 3, pp. 525–536, 2007.
[18] N. M. Bressler, W. T. Beaulieu, M. G. Maguire et al., “Early
response to anti-vascular endothelial growth factor and two-
year outcomes among eyes with diabetic macular edema in
protocol T,” American Journal of Ophthalmology, vol. 195,
pp. 93–100, 2018.
[19] R. P. Singh, K. Habbu, J. P. Ehlers, M. C. Lansang, L. Hill, and
I. Stoilov, “The impact of systemic factors on clinical response
to ranibizumab for diabetic macular edema,” Ophthalmology,
vol. 123, no. 7, pp. 1581–1587, 2016.
[20] S. B. Bressler, I. Odia, M. G. Maguire et al., “Factors associated
with visual acuity and central subfield thickness changes when
treating diabetic macular edema with anti-vascular endo-
thelial growth factor therapy: an exploratory analysis of the
protocol T randomized clinical trial,” JAMA Ophthalmol,
vol. 137, no. 4, p. 382, 2019.
[21] R. P. Singh, C. C. Wykoff, D. M. Brown et al., “Outcomes of
diabetic macular edema patients by baseline hemoglobin A1c:
analyses from VISTA and VIVID,” Ophthalmology Retina,
vol. 1, no. 5, pp. 382–388, 2017.
[22] S. E. Siegelaar, F. Holleman, J. B. L. Hoekstra, and
J. H. DeVries, “Glucose variability; does it matter?” Endocrine
Reviews, vol. 31, no. 2, pp. 171–182, 2010.
[23] H. Chehregosha, M. E. Khamseh, M. Malek, F. Hosseinpanah,
and F. Ismail-Beigi, “A view beyond HbA1c: role of con-
tinuous glucose monitoring,” Diabetes Therapy, vol. 10, no. 3,
pp. 853–863, 2019.
[24] F. Giacco and M. Brownlee, “Oxidative stress and diabetic
complications,” Circulation Research, vol. 107, no. 9,
pp. 1058–1070, 2010.