To investigate the baseline characteristics in patients with diabetic macular edema (DME) during 7 years according to the need for additional treatments after intravitreal ranibizumab (RBZ) loading injections.
The medical records of 32 patients treated with intravitreal RBZ loading for DME during 7 years were reviewed. After three-consecutive monthly RBZ injections, additional treatment was decided according to the patient’s response to RBZ loading. Based on whether the patients received treatment with or without additional injections, including intravitreal antivascular endothelial factor or steroid injection, they were divided into the “no add (NA)” or “add” groups, respectively. The baseline best-corrected visual acuity (BCVA), macular volume (MV), central subfoveal thickness, and other clinical factors were analyzed, and their 7-year changes were compared between the two groups.
The BCVA of the NA group was better than that of the add group at 2, 3, 5, and 7 years (year 2, 3, and 5;
The DME patients without additional treatments during 7 years after the initial loading treatment had shorter duration of DME and diffuse retinal thickening morphologic type with lower MV at baseline, and better long-term visual prognosis.
Diabetic macular edema (DME) is a major complication of diabetic retinopathy (DR) that causes vision impairment in adults [
Intravitreal antivascular endothelial growth factor (anti-VEGF) therapy is currently the first-line treatment for DME. Several studies have reported that initial intravitreal anti-VEGF injections in patients maintained the visual acuity and retinal structures [
Several studies demonstrated that the baseline DME types according to optical coherence tomography (OCT) patterns might be predictive factor of prognosis after RBZ injections [
In this study, a 7-year follow-up was performed for patients with DME after intravitreal RBZ loading to compare patients without additional injection (no add, NA group) and those with additional anti-VEGF or steroid injection (add group). The main outcomes measured were best-corrected visual acuity (BCVA), macular volume (MV) and central subfoveal thickness (CST). Most previous studies involved a 36-month follow-up, and there are only few reports with longer follow-up periods. This is the first 7-year follow-up study of the pro re nata treatment after RBZ loading that compares the clinical characteristics and long-term outcomes of patients with and without additional injections.
This study was conducted in accordance with the principles of the Declaration of Helsinki. The Institutional Review Board of KyungHee University Hospital approved the protocol (No. 2021-05-005). The need for informed consent was waived due to the minimal risk of divulging personal information.
This retrospective study examined 32 patients who were followed up for more than 7 years from a previous prospective case-matched comparison study at Kyung Hee University Hospital. Previous prospective study analyzed 49 of 55 patients at the 12-month follow-up with three-consecutive monthly initial RBZ loading. The medical records were analyzed retrospectively for more than 6 years. During that, additional treatment was decided according to the patient’s response to RBZ loading and recurrence of DME. The baseline variables included sex, age, duration of diabetes mellitus (DM) and DME, insulin injections, glycated hemoglobin (HbA1c) level, and BCVA, which were collected from the medical records from November 2011 to October 2021. The duration of DM was defined as the duration between diagnosis of DM and initiation of RBZ loading. The DME duration before treatment was defined as the duration between the first clinically diagnosed retinal thickening or intraretinal cyst in the posterior pole (DME signs) and initiation of RBZ loading.
In this study, 32 eyes with DME were classified into two groups, depending on whether additional injections were administered. The CST and MV measurements and DME classification were performed using Cirrus HD-OCT macular cube (512 × 128 scan mode; Carl Zeiss Meditec, Dublin, CA, USA). The DME classification according to the morphologic type in this study was based on the type that had been previously classified [
The inclusion criteria of patients enrolled in the previous study were age >18 years, vision loss caused by macular edema (ME) after DR diagnosis due to type 1 or 2 DM, BCVA between 20 / 160 and 20 / 32 on the Snellen eye chart and corresponding 39 and 78 characters of visual acuity of the Early Treatment Diabetic Retinopathy Study chart, and ≥300 μm thickness of the central macula on OCT. The exclusion criteria were presence of active endophthalmitis or intraocular infection during the follow-up period, uncontrolled glaucoma despite treatment, vitrectomy or scleral buckling performed after initial intravitreal injections, history of stroke with or without visual impairment, and untreated or posttreatment systolic blood pressure of 160 mmHg or diastolic blood pressure ≥100 mmHg.
After DME diagnosis, intravitreal RBZ injection (0.5 mg) was administered three times consecutively at 1-month intervals. An additional intravitreal anti-VEGF or steroid injection was performed when one or more of the following criteria were fulfilled during follow-up: (1) a decrease in BCVA by one line or more on the Snellen chart (equivalent to ≥5 letters score) compared to last visit, (2) increased CST more than 100 μm on OCT compared to last visit or ≥300 μm thickness of the central macula, or (3) a decrease in BCVA due to newly formed intraretinal cyst or subretinal fluid, in the opinion of the retinal specialists. Additional anti-VEGF injections included bevacizumab (Avastin; Genetech, South San Francisco, CA, USA), RBZ, and aflibercept. Furthermore, the treatment was discontinued if at least one criterion was f ulfilled of the following: no improvement in the BCVA in the last three or more consecutive visits despite intravitreal RBZ injections in the last two visits and BCVA ≥20 / 20 on the eye chart in the last two consecutive visits.
The repeated measures-analysis of variance method was used to compare the BCVA, MV, and CST at baseline and at each follow-up visit over the 7-year period, and a post hoc analysis was performed using the Bonferroni method. Comparisons of the parameters between two groups at baseline were performed using the Mann-Whitney
This study included 32 eyes of 32 patients who were followed up for over 7 years. Additional injection was not administered in 17 eyes (NA group), whereas 15 eyes received additional anti-VEGF or steroid injection (add group). The baseline characteristics are shown in
The BCVA was compared between the baseline and 1-, 2-, 3-, 5-, and 7-year follow-up. In the NA group, the BCVA improved after loading injections and maintained the improvement until the end of the follow-up. There was a significant difference in prognosis of the two groups (
The baseline MV value was significantly smaller in the NA group than in the add group (10.72 ± 0.88 mm3 vs. 11.98 ± 1.64 mm3,
During the 7 years, the CST showed a tendency to decrease, but no significant difference was found between the two groups. The initial CST in the NA and add groups was 325.71 ± 44.77 and 386.28 ± 106.79 μm, respectively. The CST in the add group tended to decrease over the 7 years. The CST was thinner in the NA group than in the add group during the 7 years (
This study investigated the differences in the baseline clinical factors and long-term outcomes between patients with or without an additional injection after initial RBZ loading in DME. We found that the baseline BCVA of the NA group was better than that of the add group, and the MV was lower. In addition, the DME duration before treatment was significantly shorter in the NA group, and the percentage of SRD or CME type was significantly lower than that in the add group. Patients without additional injection showed good response to initial RBZ loading and maintained good prognosis after ME improved. BCVA improvement in the NA group was maintained from year 2 to year 7 of the study. Interestingly, the NA group showed better BCVA prognosis than the add group, even though they did not receive additional treatment after RBZ loading.
The pathophysiology of DME involves capillary dilatation and retinal microaneurysms, accompanied by damage to the blood-retinal barrier. When the blood-retinal barrier breaks down, fluid leaks into the extracellular space and disrupts the retinal cellular structure and macular function [
Compared with the add group, the baseline MV of the NA group was significantly smaller, which was expected to be related to less severe ME. In addition, our study showed significant differences in the anatomical outcomes of MV in the early stages of the study. MV showed a decreasing trend over the follow-up period in both groups and significantly smaller MV in the NA group than in the add group until the 2nd year of the study. Patients who had better response to the initial RBZ loading had ME that improved more rapidly and maintained better retinal structure outcomes. These results corroborated the findings of several previous studies that demonstrated a reduction in the retinal thickness after anti-VEGF injections [
Another interesting finding of this study is that the DME duration before treatment was significantly shorter in the NA group than in the add group (
In this study, 73.3% of the add group and 35.2% of the NA group showed SRF or intraretinal cystic changes, which are observed in the SRD or CME types of DME, respectively. In previous reports, more than 80% cases of the DRT type of DME maintained a good response to RBZ loading without additional injections for 36 months, as compared to 33.3% cases of the CME type and 50.0% cases of the SRD type [
It was previously reported that in patients with ME, the HbA1c level was the most significant factor affecting ME, suggesting that DM control is important for a favorable treatment response [
The limitations of this study include its retrospective design which was a barrier to control the types of anti-VEGF or steroid drug in the add group. In this study, 23 patients were lost to follow-up before the 7-year period, which may have led to a selection bias. The small sample size may not be representative of all DME patients who underwent RBZ loading, and may limit the reliability of the results and unverified statistical normality when comparing the groups. Future research should address some of these limitations by incorporating a larger sample. Despite the limitations, the strength of this study was that it is the first study to compare the 7-year follow-up after initial RBZ loading in DME with and without additional injection.
In conclusion, the DME patients without additional treatments during 7 years after the initial RBZ loading treatment had shorter duration of DME. The SRD and CME type at baseline may require additional injections due to DME recurrences and be considered for closer clinical monitoring to maintain good prognosis.
None.
Diabetic macular edema based on the morphologic pattern on optical coherence tomography. (A) Diffuse retinal thickening type presents as a sponge-like swelling area with reduced retinal reflectivity. (B) Cystoid macular edema type shows intraretinal cystoid space. (C) Serous retinal detachment exhibits elevation of the retina and fluid is accumulated between the retina and retinal pigment epithelium.
Change in the mean best-corrected visual acuity (BCVA) during the 7-year follow-up period. In the no add (NA) group, the BCVA improved significantly after the loading injection. However, in the add group, the BCVA tended to recover in the 1st year but gradually decreased from the 2nd to 7th years. The NA group maintained better visual acuity than the add group did, especially showing a significant improvement after the 2nd year. logMAR = logarithm of the minimum angle of resolution.
Change in the mean macular volume (MV) during the 7-year follow-up period. Compared to the no add (NA) group, the add group showed a significant difference in the MV until the 2nd year. A smaller MV was maintained in the NA group than in the add group during the 7 years.
Change in the mean central subfield thickness (CST) during the 7-year follow-up period. In the no add (NA) and add groups, the CST gradually decreased during the follow-up period. The CST in the NA group was thinner than that in the add group during the 7 years.
Baseline characteristics and optical coherence tomography findings (n = 32)
Characteristic | No add | Add | |
---|---|---|---|
Eye | 17 (53.1) | 15 (46.9) | |
Sex | 0.467 | ||
Female | 12 (70.6) | 8 (53.3) | |
Male | 5 (29.4) | 7 (46.7) | |
Age (yr) | 68.18 ± 12.21 | 66.13 ± 7.90 | 0.243 |
Hemoglobin A1c (%) | 7.59 ± 1.02 | 8.67 ± 1.68 | 0.159 |
Diabetic retinopathy severity | 0.726 | ||
Proliferative diabetic retinopathy | 7 (41.2) | 6 (40.0) | |
Nonproliferative diabetic retinopathy | 10 (58.8) | 9 (60.0) | |
Insulin treatment | 7 (41.2) | 8 (53.3) | 0.723 |
History of laser treatment |
5 (29.4) | 6 (40.0) | 0.712 |
Duration of diabetes mellitus (yr) | 21.14 ± 6.93 | 21.36 ± 6.25 | 0.981 |
DME duration before treatment (yr) |
1.03 ± 0.98 | 1.91 ± 1.33 | 0.042 |
Extension of DME | |||
Outside the foveal area | 13 (76.5) | 14 (93.3) | 0.338 |
Type of DME | - | ||
Diffused retinal thickening | 11 (64.8) | 4 (26.7) | |
Subretinal detachment | 3 (17.6) | 5 (33.3) | |
Cystic macular edema | 3 (17.6) | 6 (40.0) | |
Blood urea nitrogen (mg/dL) | 20.18 ± 9.18 | 22.50 ± 15.90 | 0.615 |
Creatinine (mg/dL) | 0.96 ± 0.71 | 1.36 ± 2.05 | 0.710 |
eGFR (mL/min/1.73 m2) | 92.75 ± 42.24 | 89.57 ± 32.85 | 0.984 |
Hypertension treatment | 9 (52.9) | 7 (46.7) | >0.999 |
BCVA (logMAR) | 0.45 ± 0.24 | 0.50 ± 0.22 | 0.582 |
Macular volume (mm3) | 10.72 ± 0.88 | 11.98 ± 1.64 | 0.008 |
Central subfield thickness (mm) | 325.71 ± 44.77 | 386.28 ± 106.79 | 0.063 |
Inner/outer segment disruption | 4 (23.5) | 5 (33.3) | 0.699 |
Values are presented as number (%) or mean ± standard deviation.
DME = diabetic macular edema; eGFR = estimated glomerular filtration rate; BCVA = best-corrected visual acuity; logMAR = logarithm of the minimum angle of resolution.
Laser treatment including panretinal photocoagulation, focal laser, and others;
Duration between first diagnosed with DME and initiation of ranibizumab loading;
Mann-Whitney
The repeated measuresanalysis of variance method,
7-Year outcomes of BCVA and optical coherence tomography findings of diabetic macular edema
Variable | No add | Add | |||
---|---|---|---|---|---|
|
| ||||
Mean ± SD | Mean ± SD | ||||
BCVA (logMAR) | |||||
Baseline | 0.45 ± 0.24 | - | 0.50 ± 0.22 | - | 0.582 |
Year 1 | 0.30 ± 0.22 | 0.017 | 0.36 ± 0.23 | 0.544 | 0.537 |
Year 2 | 0.13 ± 0.14 | 0.001 |
0.48 ± 0.34 | 0.875 | 0.002 |
Year 3 | 0.12 ± 0.14 | 0.001 |
0.47 ± 0.34 | 0.777 | 0.002 |
Year 5 | 0.22 ± 0.24 | 0.005 |
0.54 ± 0.51 | 0.950 | 0.009 |
Year 7 | 0.29 ± 0.30 | 0.014 | 0.63 ± 0.50 | 0.591 | 0.035 |
Macular volume (mm3) | |||||
Baseline | 10.72 ± 0.88 | - | 11.98 ± 1.64 | - | 0.008 |
Year 1 | 10.19 ± 0.77 | 0.001 |
11.85 ± 1.64 | 0.400 | 0.002 |
Year 2 | 10.13 ± 0.70 | 0.001 |
11.52 ± 1.59 | 0.209 | 0.006 |
Year 3 | 9.94 ± 0.55 | 0.001 |
11.02 ± 1.83 | 0.068 | 0.044 |
Year 5 | 9.64 ± 0.52 | 0.001 |
10.16 ± 0.91 | 0.004 |
0.135 |
Year 7 | 9.64 ± 0.80 | 0.020 | 10.01 ± 1.51 | 0.002 |
0.648 |
Central subfield thickness (mm) | |||||
Baseline | 325.71 ± 44.77 | - | 386.28 ± 106.79 | - | 0.063 |
Year 1 | 272.79 ± 40.85 | 0.028 | 294.14 ± 76.79 | 0.004 |
0.581 |
Year 2 | 261.86 ± 30.95 | 0.003 |
332.36 ± 113.73 | 0.159 | 0.060 |
Year 3 | 252.93 ± 24.88 | 0.001 |
317.64 ± 117.97 | 0.045 | 0.048 |
Year 5 | 240.88 ± 19.34 | 0.001 |
271.86 ± 84.39 | 0.007 |
0.334 |
Year 7 | 231.86 ± 24.35 | 0.001 |
257.50 ± 65.36 | 0.001 |
0.383 |
The repeated measures-analysis of variance method was used to compare both groups and changes between baseline and follow-ups.
The post hoc analysis was performed using the Bonferroni method.
BCVA = best-corrected visual acuity; SD = standard deviation; logMAR = logarithm of the minimum angle of resolution.
After treatment versus baseline;
Statistically significant,
Statistically significant,