Review Article: Intravitreal Therapy For Diabetic Macular Edema: An Update

Hindawi
Journal of Ophthalmology
Volume 2021, Article ID 6654168, 23 pages
https://doi.org/10.1155/2021/6654168
Review Article
Intravitreal Therapy for Diabetic Macular Edema: An Update
Claudio Furino ,1 Francesco Boscia ,1 Michele Reibaldi ,2 and Giovanni Alessio 1
1
Department of Medical Science, Neuroscience and Sense Organs, Eye Clinic, University of Bari,
Azienda Ospedaliero-Universitaria Policlinico Bari, Bari, Italy
2
Department of Surgical Sciences, Eye Clinic, University of Torino, Torino, Italy
Correspondence should be addressed to Claudio Furino; claudiofurino@gmail.com
Received 14 November 2020; Revised 11 February 2021; Accepted 16 February 2021; Published 23 February 2021
Academic Editor: Enrique Mencı́a-Gutiérrez
Copyright © 2021 Claudio Furino 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.
Diabetic macular edema (DME) represents a prevalent and disabling eye condition. Despite that DME represents a sight-
threatening condition, it is also among the most accessible to treatment. Many different treatment options including photo-
coagulation, intravitreal medical treatment (either vascular endothelial growth factor inhibitors or corticosteroids therapies), and
surgical removal are currently available. Although laser has been considered as the gold standard for many years, over the past
several years vascular endothelial growth factor inhibitors (anti-VEGFs) have become first-line therapy. However, many patients
do not adequately respond to them. With the development of sustained-release corticosteroid devices, steroids have gained a
presence in the management of the DME. We review and update the role of anti-VEGF and intravitreal sustained-release
corticosteroid management of DME. According to the currently available scientific evidence, the choice of one anti-VEGF over
another critically depends on the baseline best-corrected visual acuity (BCVA). While aflibercept may be the drug of choice in low
baseline BCVA, the three anti-VEGFs (bevacizumab, ranibizumab, and aflibercept) provided similar functional outcomes when
the baseline BCVA was higher. DEX implants are a valuable option for treating DME, although they are usually seen as a second
choice, particularly in those eyes that have an insufficient response to anti-VEGF. The new evidence suggested that, in eyes that did
not adequately respond to anti-VEGF, switching to a DEX implant at the time to 3 monthly anti-VEGF injections provided better
functional outcomes.
1. Introduction Despite that DME represents a sight-threatening con-

dition, it is also among the most accessible to treatment.
Because the prevalence of diabetes is rising, the relevance of Many different treatment options including laser photoco-
diabetic eye disease increases [1, 2]. In Europe, it was es- agulation, intravitreal medical treatment (either vascular
timated that approximately 6.4 million people are currently endothelial growth factor inhibitors or corticosteroids
affected by any diabetic eye disease and 8.6 million people therapies), and pars plana vitrectomy [6] are currently
will be affected in 2050 [3]. In the year 2020, moderate to available.
severe visual impairment due to diabetic retinopathy has A retrospective analysis, conducted on a population of
been estimated in 4.06% (Western Europe), 4.77% (Asia- 13,410 treatment-naı̈ve DME patients, has found that the
Pacific, high income), and 4.99% (United States, high in- treatment patterns within 28 days of initial DME diagnosis
come) [2]. were as follows: observation in 9,990 (74.5%) patients,
Diabetic macular edema (DME) is a chronic, multifac- vascular endothelial growth factor inhibitors (anti-VEGFs)
torial, and sight-threatening condition that critically impacts in 2,086 (15.6%) patients, laser in 1,133 (8.4%) patients,
patients’ quality of life [4, 5]. corticosteroids in 133 (1.0%) patients, and combined
The prevalence of any DME in Europe was 3.7% and its treatment in 68 (0.5%) patients [7].
pooled mean annual incidence in type 2 diabetes patients The main purpose of this paper was to review the role of
was 0.4% [3]. anti-VEGF and intravitreal sustained-release corticosteroid
2 Journal of Ophthalmology
devices for treating patients with DME. Additionally, this 3.1. Vascular Endothelial Growth Factor Inhibitors. The in-
paper is also going to evaluate the current evidence about the troduction of anti-VEGF agents has revolutionized the
convenience of switching to intravitreal dexamethasone medical management of DME. Under the umbrella of the
implant in those patients with suboptimal response to anti- term “anti-VEGF,” there are several different molecules that
VEGF therapies. can be classified as aptamers (pegaptanib), antibodies to
VEGF (bevacizumab), antibody fragments to VEGF (rani-
bizumab), and fusion proteins, which combine a receptor for
2. Pathophysiology VEGF with the constant region of a human immunoglobulin
A complete review of the pathophysiologic mechanisms in (aflibercept and conbercept) [14, 15].
DME is beyond the scope of this paper.
Macular edema (ME) is defined as an abnormal increase
of fluid volume in the macula [8]. The etiology and path- ®
3.1.1. Pegaptanib. Pegaptanib (Macugen , Bausch and
Lomb, Rochester, NY, USA), developed to bind and block
ogenesis of DME are multifactorial and result from multiple
and intricate mechanisms. Although hyperglycemia is the the activity of extracellular VEGF [16, 17], was the first
main risk factor for diabetic retinopathy, different factors commercially available anti-VEGF drug used to treat DME
including hypoxia, impaired blood flow, retinal ischemia, [17]. Cunningham et al. [17] in a randomized, double-
and inflammation are also associated with DME [8, 9]. masked, multicenter, dose-ranging, and sham-controlled
Different molecules such as interleukin-6 (IL-6), IL-8, phase II trial evaluated the efficacy and safety of pegaptanib
IL-1B, vascular endothelial growth factor (VEGF), and tu- in the treatment of DME. Three different doses of pegaptanib
mor necrosis factor-α (TNF-α ) are upregulated in eyes with (0.3 mg, 1.0 mg, and 3.0 mg) were tested and compared to
DME [9, 10]. These mechanisms cause a disruption of the sham injections. Injections were planned at baseline, week 6,
blood-retinal barrier that not only leads to the accumulation and week 12, with additional injections and/or focal pho-
of subretinal and intraretinal fluid but also stimulates the tocoagulation as needed for another 18 weeks [17]. At week
expression of adhesion molecules that facilitate the adhesion 36 compared with baseline, visual acuity improvement ≥10
capacity of inflammatory cells [9, 10]. letters occurred in 15 of 44 (34%) patients, 13 of 43 (30%)
Recent investigations have shown that chronic hyper- patients, 6 of 42 (14%) patients, and 4 of 41 (10%) patients in
glycemia induces oxidative stress and inflammation in the the 0.3 mg, 1.0 mg, 3.0 mg, and sham subgroups, respectively
retina, which constitutes early processes in the development (p � 0.003, 0.3 mg versus sham) [17].
of DME [8, 11]. Increased inflammation is associated with Sultan et al. [18] evaluated in a randomized (1 : 1), sham-
capillary nonperfusion and breakdown of the blood-retina controlled, multicenter, parallel-group clinical trial the ef-
barrier [8, 10, 11]. Inflammation is not only a consequence of ficacy and safety of intravitreal pegaptanib 0.3 mg versus
barrier dysfunction but also an early local mechanism sham injections. Based on the results of this study, the
contributing to barrier alteration and leukostasis [8, 10, 11]. probability of achieving a visual acuity improvement of ≥10
Inflammatory cytokines, which mediate vascular per- letters, at week 54 compared with baseline, was significantly
meability, such as tumor necrosis factors alpha and beta, greater in the pegaptanib group (odds ratio, 2.38; 95%
alpha 4 integrin, nitric oxide, and interleukin-1β are elevated confidence interval, 1.32–4.30; p � 0.0047) [18].
in DME [8–11] (Figure 1). Additionally, the results of a Japanese phase III ran-
domized clinical trial found that the proportion of patients
who achieved a visual acuity improvement of ≥10 letters,
3. Treatment Strategies of DME from baseline to week 24, was significantly greater in the
pegaptanib group (20.3%) than in the sham group (5%),
Although laser treatment has been considered as the gold p � 0.0003) [19].
standard for many years [12, 13], according to the European The results of these randomized clinical trials have been
Society of Retina Specialists (EURETINA) guidelines, focal/ confirmed in several studies conducted in clinical settings
grid laser is now reserved mostly for non-center-involving [20–22].
DME [6]. Similarly, the results of a retrospective study, which
Currently, anti-VEGF agents are considered the first line evaluated the effect of intravitreal pegaptanib on the func-
of treatment in center-involving DME; however, all the large tional and anatomical outcomes, found a significant im-
clinical trials have shown that only 33–45% of DME patients provement (from baseline to the last follow-up visit) in mean
on anti-VEGF agents show 3 lines or more of visual im- BCVA and a significant reduction in central macular
provement [6, 14, 15]. The inadequate response to anti- thickness (CMT) (p < 0.001 and p < 0.001, respectively) [20].
VEGF observed in many patients speaks in favor of the Rinaldi et al. [21] published in 2012 a longitudinal,
presence of other factors beyond VEGF, such as inflam- interventional, and nonrandomized study that evaluated the
mation, which is not targeted by the anti-VEGF drugs. There efficacy and safety of intravitreal pegaptanib in patients with
is, therefore, a need for supplemental treatments that might “clinically significant diabetic macular edema”. The results of
improve visual acuity in eyes with persistent edema despite this study found a significant reduction in foveal thickness
anti-VEGF therapy. (p � 0.0001) and a significant improvement in BCVA
An overview of the currently available and future options (p < 0.005), macular sensitivity (p < 0.001), and color dis-
for treating DME is summarized in Figure 2. crimination (p � 0.0001) [21].
Journal of Ophthalmology 3
Diabetes mellitus
Glutamate Hyperglycemia LDL
ROS
OxiLDL
ICAM-1
ROS Polyol AGEs PKC

VEGF
Proinflammatory agents PEDF

Apoptotic factors
Adhesion molecules: ICAM-1; VCAM-1; selectins;
and integrins Chemokines: MCP-1(CCL2); Ang 2; IL-8;
and osteopontin Cytokines: IL-61; IL-6; IL-12; and TNF-α
Activation of microglia + Müllercells + astrocytes Cell apoptosis +

retinal ischemia
Low-grade inflammation of the retina
Endothelial cells and pericytes degeneration Blood-retinal barrier dysfunction
Diabetic retinopathy
DME
Figure 1: An overview of the different pathways involved in the development of diabetic macular edema (adapted from Daruich et al. [8]
and Romero-Aroca et al. [9]). LDL: low-density lipoprotein; ROS: reactive oxidative species; Oxi: oxidized; AGEs: advanced glycation end-
products; PKC: protein kinase C; ICAM-1: inflammatory intercellular adhesion molecule-1; VEGF: vascular endothelial growth factor;
VCAM-1: vascular cell adhesion molecule-1; PEDF: pigment epithelium-derived factor; CCL2: chemokine C-C motif ligand 2; Ang-2:
angiopoietin-2; IL: interleukin; TNF: tumor necrosis factor; DME: diabetic macular edema.
(i) Pegaptanib; Bevacizumab; Ranibizumab; Aflibercept; Conbercept;

Anti-VEGF
Brolicizumab; VEGF DARPin.
(ii) Steroids (triamcinolone acetonide; dexamethasone; fluocinolone

Anti-inflammatory
acetonide); Betamethasone microspheres; Loteprednol; Danazol.
(iii) Aspirin; nepafenac; bromfenac; diclofenac, and other NSAID

NSAIDs
(such as indomethacin).
Inhibitors of multiple (iv) Sirolimus (mTOR); PF-655 (RTP 801 gene); iCo-007 (cRaf kinase);
growth factors Squalamine; anti-bFGF; anti-PDGF.
Cytokine and (v) Infliximab; Inhibitors of angiotensin-2; CCR2-CCR5 inhibitor;

chemokine inhibitors minocycline; KK-inhibitor
Others (vi) Exenatide; lanreotide; IGF-1R blocker; EPO; mecamylamine
Figure 2: Overview of the medical treatment options for diabetic macular edema (adapted from Urias et al. [15]). NSAIDS: nonsteroidal
anti-inflammatory drug; VEGF: vascular endothelial growth factor; DARPin: designed ankyrin repeat protein; FGF: fibroblast growth factor
beta; PDGF: platelet-derived growth factor; CCR: chemokine receptor; IGF-1: insulin-like growth factor-1; EPO: erythropoietin.
Sivaprasad et al. [22], in an open-label, one-year, and achieved a visual acuity improvement of ≥ 10 letters and 8
noncomparative study, evaluated the safety and tolerability (8.7%) of 46 patients reported treatment-related adverse
of pegaptanib in DME patients. Four (25%) of 12 patients events [22].
3.1.2. Bevacizumab. Bevacizumab, a humanized monoclo- (p � 0.03). However, this advantage was not considered as
nal antibody that inhibits vascular endothelial growth factor clinically relevant because the effect of visual acuity varied
(VEGF), was originally developed as a concomitant medi- according to the baseline visual acuity [35]. As regards
cation for use in combination with existing metastatic co- central subfield thickness, aflibercept achieved the greatest
lorectal cancer regimens [23]. reduction with 169 ± 138 μm (p < 0.001 vs. bevacizumab and
Intravitreal injections of bevacizumab have been and p � 0.0336 vs. ranibizumab), followed by ranibizumab with
currently continue to be widely used as an off-label treat- 147 ± 134 μm (p < 0.001 vs. bevacizumab) and bevacizumab
ment for neovascular age-related macular degeneration and with 101 ± 121 μm. However, similarly to visual acuity, the
DME [6, 7, 14, 15]. effect on central subfield thickness varied according to initial
The first study evaluating the efficacy of bevacizumab visual acuity [35].
(Avastin; Genentech, Inc., South San Francisco, CA) for the The main findings of the Protocol T are shown in Table 2.
treatment of persistent DME was published by Haritoglou The 2-year Protocol T results showed slight changes as
et al. [24]. The results of this prospective, consecutive, and compared to the 1-year results. However, as shown in the 1-
noncomparative case series study found a significant im- year results, BCVA improvement varied according to the
provement in visual acuity (p � 0.001) and a significant initial visual acuity [36].
reduction in CMT (p � 0.002) [24].
These findings were confirmed by different small studies (1) Safety. Many ophthalmologists have been and currently
[25–28]. are worried about the safety profile of bevacizumab. When
The Diabetic Retinopathy Clinical Research Network used to treat certain cancers, intravenous bevacizumab has
(DRCR.net) published in 2007 the results of a randomized been associated with several side effects, including systemic
phase II clinical trial that evaluated the efficacy and safety of hypertension, proteinuria, and cardiovascular and gastro-
intravitreal bevacizumab (either alone or in combination intestinal complications [37].
with focal photocoagulation) in DME patients [29]. The The results of a post hoc analysis of the Protocol T found
results of this study suggested some positive findings as- that aflibercept and bevacizumab induced greater decreases
sociated with the use of bevacizumab. However, this re- in plasma free-VEGF than ranibizumab at 4 weeks [38].
sponse was similar to that observed in the laser group after Moreover, at 52 and 104 weeks, a greater decrease was
more than 3 weeks [29]. observed in bevacizumab versus ranibizumab [38]. Inter-
The BOLT (bevacizumab or laser therapy) study was a estingly, this study did not find any significant relationship
prospective, randomized, masked, single-center, 2-year, and between VEGF concentration and the incidence of a heart
2-arm clinical trial that compared the effect of repeated attack or stroke [28].
intravitreal injections of bevacizumab versus (vs.) modified The incidence of serious ocular and nonocular adverse
Early Treatment of Diabetic Retinopathy Study (ETDRS) events was approximately below 1 per 100 injections for
macular laser therapy in patients with persistent clinically intravitreal bevacizumab [28–36]. Several systemic adverse
significant DME [30]. The results of this study found that, events have been reported in different studies, including
after 12 months of follow-up, the probability of achieving a systemic hypertension, cerebrovascular accidents, heart at-
visual acuity improvement of ≥10 ETDRS letters was sig- tacks, and death [28–36, 39–41]. Ocular side effects included
nificantly greater in the bevacizumab group than in the laser bacterial endophthalmitis, ocular inflammation (iritis, iri-
group (adjusted odds ratio, 5.1; 95% confidence interval, 1.3 docyclitis, uveitis, or vitreous), tractional retinal detach-
to 19.7, p � 0.019) [30]. ment, pigmentary epithelial detachment, vitreous
The 2-year outcomes of the BOLT study confirmed the hemorrhage, ocular hypertension, and cataract
aforementioned 12-month data [30]. At 2 years, the pro- [28–36, 39–41].
portion of patients gained ≥10 or ≥15 ETDRS letters was According to the European Society of Retina Specialists
significantly greater in the bevacizumab group than in the (EURETINA) guidelines, there are still some issues about the
laser one (p � 0.001 and p � 0.004, respectively) [31]. anti-VEGF safety profile of bevacizumab that should be
Different randomized clinical trials (RCTs), whose re- further explored [6].
sults have been summarized in Table 1, have evaluated the
efficacy and safety of intravitreal bevacizumab in DME
patients [29–34]. Although, on average, intravitreal bev-
acizumab has shown a positive impact on DME patients, in
®
3.1.3. Ranibizumab. Ranibizumab (Lucentis , Novartis,
Basel, Switzerland) is a fully humanized monoclonal anti-
many studies it was not superior to other therapies. body fragment, which binds to multiple variants of VEGF-A
The Protocol T was a prospective, randomized, and [42]. It was originally approved for treating neovascular age-
multicenter clinical trial that compared the efficacy and related macular degeneration [6].
safety of intravitreal injections of bevacizumab, ranibizu- The first prospective, randomized, interventional, and
mab, and aflibercept for the treatment of DME [35]. Patients multicenter clinical trial comparing the effect of ranibizu-
included in Protocol T were randomly assigned in a 1 : 1 : 1 mab with focal/grid laser or a combination of both in DME
ratio to be injected with bevacizumab (1.25 mg), ranibizu- was the Ranibizumab for Edema of the mAcula in diabetes
mab (0.3 mg), or aflibercept (2.0 mg) [35]. The mean visual (READ-2) study [43]. Patients were randomly assigned in a
acuity improvement was significantly greater with afli- 1 : 1 : 1 regime to receive ranibizumab 0.5 mg (baseline and
bercept than with bevacizumab (p < 0.001) and ranibizumab months 1, 3, and 5), laser (baseline and month 3, if needed),
Table 1: Overview of the functional and anatomic results of bevacizumab.
Duration N BCVA (ETDRS letters) CRT (µm)

Study Ref. Regimen
(w) (eyes) Baseline Changea Baseline Change
Laser 19 64 (50 to 70) −1 (−6 to 5) 441 (354 to 512) −40 (−146 to 85)
Beva I 22 65 (60 to 70) 5 (1 to 12)∗ 397 (320 to 358) −56 (−120 to −6)
DRCR.neta [29] 12 Beva II 24 63 (57 to 71) 7 (4 to 11)∗ 446 (342 to 543) −47 (−125 to −16)
Beva III 22 64 (52 to 68) 4 (−3 to 7) 406 (353 to 520) −5 (−41 to 53)
Beva IV 22 66 (57 to 72) 0 (−5 to 8) 389 (308 to 452) −40 (−103 to 33)
Beva
42 55.7 (9.7) 8 (1 to 10)∗∗ 507 (145) −130 (122)
[30] 52 1.25 mg
Laser 38 54.6 (8.6) −0.5 (−15 to 5) 481 (121) −68 (171)
BOLTb
Beva ∗∗
42 55.7 (9.7) 8.6 507 (145) −146
[31] 104 1.25 mg
Laser 38 54.6 (8.6) 0.5 481 (121) −118
Nepomuceno Beva 1.5 mg 32 0.60 (0.05) 0.36 (0.05) 451.7 (22.3) −122.0 (20.9)
[32] 48
et al.c Rani 0.5 mg 28 0.63 (0.06) 0.34 (0.04) 421.9 (23.1) −141.0 (18.6)
Kriechbaum Beva 2.5 mg 15 0.30 (0.19 to 0.42) 0.18 (0.06 to 0.3) 505 (438 to 572) 351 (258 to 445)
[33] 52
et al.c Triam 8 mg 15 0.32 (0.2 to 0.43) 0.36 (0.19 to 0.52) 490 (433 to 547) 296 (224 to 368)
Beva
26 0.48 (0.32) 0.40 (0.25) 495.7 (195.3) 449.7 (212.2)
Sonoda et al.c [34] 12 1.25 mg
Triam 4 mg 25 0.40 (0.25) 0.31 (0.23) 503.9 (171.4) 389.4 (209.4)
Note. aData are expressed in median (interquartile range). bData are expressed in mean (standard deviation). cMean (standard deviation) best-corrected visual
acuity (logMAR) at baseline and at the last follow-up visit. ∗ p < 0.01 vs. laser. ∗∗ p < 0.001 vs. laser. w: weeks; BCVA: best-corrected visual acuity; EDTRS: Early
Treatment of Diabetic Retinopathy Study; CRT: central retina thickness; DRCR.net: Diabetic Retinopathy Clinical Research Network; Beva I: intravitreal
injection of 1.25 mg of bevacizumab at baseline and 6 weeks; Beva II: intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks; Beva III:
intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks; Beva IV: intravitreal injection of 1.25 mg of bevacizumab at baseline
and 6 weeks with photocoagulation at 3 weeks; Beva: bevacizumab; Rani: ranibizumab; Triam: triamcinolone acetonide.
Table 2: Overview of the visual acuity outcomes of the Protocol T.

Aflibercept vs. Aflibercept vs. Ranibizumab vs.
Visual acuity letter bevacizumab ranibizumab bevacizumab
score and Snellen Aflibercept Bevacizumab Ranibizumab
equivalent Difference (95% p Difference p Difference p
CI) valuea (95% CI) valuea (95% CI) valuea
Letter score of <69, equivalent to 20/50 or worse, at baseline
Number of eyes 102 102 101
Visual acuity at baseline
Mean (SD)
56.2 (11.1) 56.6 (10.6) 56.5 (9.9)
letter score
Approximate
Snellen 20/80 20/80 20/80
equivalent
Visual acuity at 1 year
Mean (SD)
75.2 (10.9) 68.5 (13.6) 70.7 (12.0)
letter score
Approximate
Snellen 20/32 20/40 20/40
equivalent
Change from baseline in letter score
Mean (SD) 1.8
18.9 (11.5) 11.8 (12.0) 14.2 (10.6) 6.5 (2.9 to 10.1) <0.001 4.7 (1.4 to 8.0) 0.003 0.21
improvement (−1.1 to 4.8)
Improvement
of ≥10 letters, 79 (77) 61 (60) 70 (69) 17 (2 to 31) 0.02 10 (−4 to 23) 0.20 7 (−6 to 20) 0.28
n (%)
Worsening of
≥10 letters, n 1 (1) 4 (4) 2 (2) −3 (−7 to 2) 0.56 −1 (−5 to 3) 0.56 −1 (−6 to 3) 0.56
(%)
Improvement
of ≥15 letters, 68 (67) 42 (41) 50 (50) 24 (9 to 39) <0.001 18 (4 to 32) 0.008 6 (−7 to 19) 0.34
n (%)
Table 2: Continued.
Aflibercept vs. Aflibercept vs. Ranibizumab vs.
Visual acuity letter bevacizumab ranibizumab bevacizumab
score and Snellen Aflibercept Bevacizumab Ranibizumab
equivalent Difference (95% p Difference p Difference p
CI) valuea (95% CI) valuea (95% CI) valuea
Worsening of
≥15 letters, n 1 (1) 2 (2) 2 (2) 0 (−3 to 3) 0.85 −1 (−4 to 2) 0.85 1 (−3 to 4) 0.85
(%)
Letter score of 78 to 69, equivalent to 20/32 to 20/40, at baseline
Number of eyes 106 104 105
Visual acuity at baseline
Mean (SD)
73.5 (2.6) 72.8 (2.9) 73.4 (2.7)
letter score
Approximate
Snellen 20/32 20/40 20/40
equivalent
Visual acuity at 1 year
Mean (SD)
81.4 (8.3) 79.9 (10.1) 81.6 (6.8)
letter score
Approximate
Snellen 20/25 20/25 20/25
equivalent
Change from baseline in letter score
Mean (SD) −0.4 (−2.3 to 1.1 (−0.9 to
8.0 (7.6) 7.5 (7.4) 8.3 (6.8) 0.7 (−1.3 to 2.7) 0.69 0.69 0.69
improvement 1.5) 3.1)
Improvement
of ≥10 letters, 53 (50) 47 (45) 52 (50) 6 (−9 to 21) 0.82 0 (−13 to 14) 0.95 6 (−10 to 21) 0.82
n (%)
Worsening of
≥10 letters, n 4 (4) 2 (2) 1 (1) 2 (−3 to 6) 0.54 3 (−1 to 7) 0.54 −1 (−4 to 2) 0.54
(%)
Improvement
of ≥15 letters, 19 (18) 17 (16) 16 (15) 2 (−7 to 11) 0.73 4 (−5 to 12) 0.73 −2 (−10 to 7) 0.73
n (%)
Worsening of
≥15 letters, n 2 (2) 1 (1) 1 (1) 1 (−2 to 4) 0.99 1 (−2 to 4) 0.99 0 (−3 to 3) 0.99
(%)
a
Treatment group comparisons were performed with ANCOVA models adjusted for continuous baseline visual acuity or from binomial regression models
adjusted for categorical baseline visual acuity (adapted from Diabetic Retinopathy Clinical Research Network et al. [29]). CI: confidence interval; SD: standard
deviation; n � number.
and a combination of ranibizumab 0.5 mg and laser (baseline profile, there were no significant differences in the incidence
and month 3) [43]. The results of this study found that, at of serious and nonserious ocular/nonocular adverse events
month 6, BCVA improvement was significantly greater in between ranibizumab and sham. In both arms (without
those eyes receiving ranibizumab alone (p � 0.01). significant differences between them), the most frequently
The RESOLVE was a 12-month, multicenter, sham- reported adverse events were conjunctival hemorrhage,
controlled, double-masked study designed to evaluate the ocular hypertension, and eye pain [44].
efficacy and safety of ranibizumab in DME [44]. Study The RESTORE study was a 12-month, multicenter,
patients were randomized to ranibizumab (0.3 or 0.5 mg; prospective, randomized, double-masked, and laser-con-
n � 51 each) or sham (n � 49) [44]. The mean average change trolled phase III study that evaluated the efficacy (in terms of
in BCVA from month 1 to month 12 was significantly BCVA improvement) of ranibizumab 0.5 mg + sham laser
greater with ranibizumab (7.8 letters) than with sham (−0.1 vs. ranibizumab + laser vs. laser alone [45]. As compared to
letters) (p < 0.0001). Similarly, the mean change in CMT was laser, ranibizumab alone achieved a greater BCVA im-
significantly greater with ranibizumab (−194.2 μm) than provement (p < 0.0001) and a greater proportion of gaining
with sham (−48.4 μm) (p < 0.001) [44]. Regarding the safety ≥15 letters (p � 0.0005). CMT reduction was significantly
greater with ranibizumab alone than with laser alone The long-term (three years) outcomes of the RISE and
(p < 0.0001). There were no significant differences in either RIDE studies were published in 2013 [49]. RISE and RIDE
BCVA improvement or CMT reduction between ranibizu- were two phase III, multicenter clinical trials that were
mab alone and ranibizumab + laser. Regarding the safety sham-controlled for two years. Patients were randomly
profile, there was no significant association between rani- assigned in a 1 : 1 regime to monthly sham injection or
bizumab (alone or in combination) and the incidence of intravitreal ranibizumab (either 0.3 or 0.5 mg) during a
cardiovascular or cerebrovascular events [45]. follow-up period of two years. In the third year, sham pa-
Based on the RESTORE results, the European Medicines tients, while still masked, were eligible to crossover to
Agency (EMAs) approved in 2011 the use of ranibizumab for monthly 0.5 mg ranibizumab [49]. Functional outcomes at
the treatment of DME [6]. Interestingly, the dose approved month 36 observed in the ranibizumab groups were in line
by the EMAs (0.5 mg) differs from those approved by the with those previously reported in the two-year follow-up
Food and Drug Administration (0.3 mg) [6]. study [46]. The proportion of patients achieving a gaining
The RISE and the RIDE are two multicenter, prospective, ≥15 letters in BCVA was greater, in both RISE and RIDE, in
randomized, and sham injection-controlled studies that the ranibizumab groups (independently of the dose) than in
evaluated the efficacy and safety of ranibizumab in DME the sham group [49]. Patients who previously received sham
patients [46]. Seven hundred and fifty-nine patients (377 in when were changed to ranibizumab 0.5 showed lower BCVA
RISE and 382 in RIDE) were randomized to receive monthly improvements than those obtained by ranibizumab after
sham injections or intravitreal injections of ranibizumab their first year of treatment [49]. The incidence of serious
0.3 mg or 0.5 mg. The proportion of patients gaining ≥15 adverse events potentially related to systemic VEGF inhi-
letters in RISE was the 18.1 %, 39.2%, and 44.8% in eyes bition was 19.7% and 16.8% in eyes treated with ranibizu-
treated with sham, ranibizumab 0.5 mg, and ranibizumab mab 0.3 mg and 0.5 mg, respectively [49].
0.3 mg, respectively (p < 0.0001 between sham and 0.3 mg The RESTORE extension evaluated the results of the
and p � 0.0002 between sham and 0.5 mg) [46]. Regarding protocol RESTORE after three years of follow-up. The
RIDE, a greater proportion of patients achieved a BCVA RESTORE had a 12-month double-masked phase and a 24-
improvement ≥15 in the ranibizumab 0.3 mg group (33.6%, month open-label extension [50]. 79% (240/303) of the
p < 0.0001 vs. sham) and in the ranibizumab 0.5 mg group patients who completed the first phase of the RESTORE were
(45.7%, p < 0.0001 vs. sham) than in the sham-treated group included in the extension, and 208 patients (86.7%) com-
(12.3%). BCVA improvements were paralleled by rapid pleted the extension study. In those patients previously
reductions in CMT. Independently of the study (RISE or treated with ranibizumab during the 12-month double-
RIDE) and the ranibizumab dose (0.3 or 0.5), the mean CMT masked phase, BCVA improvement and CMT reduction
reduction was significantly greater in ranibizumab groups were maintained. In the laser group, when ranibizumab
than in sham groups (p < 0.0001 each) [46]. Safety profile intravitreal injections were allowed, there were a BCVA
showed that serious adverse events were uncommon and improvement (+6.0 letters) and a retinal thickness reduction
included one case of endophthalmitis in RISE and 3 in RIDE (−142.7 μm) at month 36. Cataract, with an incidence of
and 2 cases of traumatic cataract in RISE and one in RIDE. 16.3%, was the most frequently reported adverse event. Eight
Systemic adverse events potentially related to systemic patients died during the study; none were suspected to be
VEGF inhibitions occurred in 10.6% and 9.4% of sham- related to the study drug/procedure [50].
treated patients in RISE and RIDE, respectively, and in 5.6% The LUCIDATE study was a prospective, randomized,
and 1.9% of ranibizumab-treated eyes (both doses) across single-masked, and single-center clinical trial that compared
the studies [46]. the functional and anatomical effects of laser versus ranibi-
The 3-year follow-up results of the study that evaluated zumab in DME patients [51]. Patients were randomly
the effect of prompt vs. deferred (≥24 weeks) of laser assigned in a 2 : 1 ratio to 3 monthly doses of ranibizumab and
treatment in eyes receiving intravitreal injections of intra- retreatment when needed vs. laser at baseline and repeated
vitreal ranibizumab (0.5 mg) suggested that, in eyes with every 12 weeks (as needed) [51]. Mean BCVA improvement
DME, deferring laser ≥ 24 weeks provided better functional was +6.0 letters in the ranibizumab group vs. −0.9 letters in
outcomes than prompt laser treatment [47]. However, this the laser group. Additionally, retinal sensitivity and electro-
finding might be justified by the fact that eyes that received physiology function were improved with ranibizumab. An-
prompt laser received fewer ranibizumab injections than atomic outcomes were better in the ranibizumab group than
needed [47]. in the laser group. No safety issues were reported [51].
The extension from 24 to 36 months of the READ study The 5-year results of the DRCR.net study evaluating
found that, in the ranibizumab group, the variation in BCVA ranibizumab plus prompt or deferred laser or triamcinolone
from month 24 to month 36 was +3.1 letters (p � 0.009) and plus prompt laser for diabetic macular edema suggested that,
foveal thickness was thinner at month 36 than at month 24 in eyes with DME, focal/grid laser treatment at the initiation
(mean variation −70 microns, p � 0.006) [48]. The results of of intravitreal ranibizumab treatment did not provide better
this study found that although long-term functional and results than deferring laser treatment for ≥24 weeks [52].
anatomical outcomes with ranibizumab were very good, Additionally, deferring laser was also associated with an
many patients required frequent injections to achieve such increase in the number of intravitreal injections of ranibi-
outcomes [48]. zumab [52].
The REVEAL study was a 12-month, randomized, poor early response was associated with a poor long-term
double-masked, multicenter, laser-controlled, phase III visual outcome. Additionally, this study found that 39.7% of
study conducted in the Asian population that compared the the eyes underwent ranibizumab (with or without laser) did
efficacy of three different therapeutic strategies: ranibizu- not adequately respond (BCVA improvement < 5 letters) at
mab + sham laser, ranibizumab + active laser, or sham week 12 [59].
injection + active laser [53]. Ranibizumab alone or in The two-year effectiveness of intravitreal ranibizumab in
combination with laser provided better functional and an- combination with a nutritional supplement rich in docosa-
atomic outcomes than laser alone. The most frequently hexaenoic acid plus antioxidants was evaluated in a prospective,
reported ocular adverse event was conjunctival hemorrhage. randomized, and single-blind controlled study [60]. At month
There was no evidence of adverse events associated with 24, the combined therapy provided a statistically significant
systemic inhibition of VEGF [53]. CMT reduction as compared with intravitreal ranibizumab
The RELIGHT study evaluated the potential benefits of alone. However, there were no significant differences in BCVA
tailoring the ranibizumab treatment regime to the DME improvement between the two strategies [60].
patient’s needs [54]. Patients received initially a loading dose The TREX-DME study was a multicenter, prospective,
of 3 initial intravitreal ranibizumab injections (baseline and and randomized clinical trial designed for comparing
months 1 and 2). Based on individualized BCVA and CMT, monthly ranibizumab injections vs. an incremental exten-
patients received monthly intravitreal ranibizumab injec- sion algorithm [61]. The results of this study suggested that
tions (months 3 to 5) and bimonthly between months 6 and the incremental extension strategy did not provide worse
18 [54]. The results of this study suggested that functional functional or anatomic outcomes, while decreasing the
outcomes obtained during the initial 6-month treatment number of injections administered [61].
regime were maintained during the bimonthly tailored The ROTATE trial was a prospective and open-label
treatment [54]. study that evaluates the efficacy of intravitreal of ranibizu-
Similarly, the RETAIN study was designed to evaluate mab 0.3 mg in eyes with persistent DME after intravitreal
whether an incremental extension of intertreatment inter- bevacizumab treatment [62]. The results of this study
vals (1 to 3 months) would be feasible [55]. In terms of showed that the mean BCVA was significantly improved
functional outcomes, the incremental extension regimen did (+6.5 letters) and CMT was significantly reduced (−116 µm)
not provide worse results than a standard pro re nata (PRN) under intravitreal ranibizumab treatment. On the negative
regime (monthly followed and treated according to signs of side, systemic adverse events included two deaths, stroke,
disease activity). However, the number of intravitreal in- and myocardial infarction [62].
jections was slightly greater with the incremental extension The RELATION study, a prospective, double-masked,
regimen [55]. multicenter phase IIIb trial, assessed the efficacy and safety
The READ-3 study was a multicenter, prospective, and of intravitreal ranibizumab 0.5 mg plus laser versus laser
randomized study that compared the efficacy of intravitreal monotherapy in patients with DME [63]. As compared with
injections of ranibizumab 2.0 mg with ranibizumab 0.5 mg laser monotherapy, ranibizumab + laser provided a signifi-
in eyes with DME [56]. The results of this study suggested cantly greater BCVA improvement (mean difference be-
that BCVA improvement was not superior with ranibizu- tween groups, 4.2 letters; p � 0.001). However, there was no
mab 2.0 mg than with ranibizumab 0.5 mg. The safety profile significant difference in CMT reduction between the two
of both doses was similar [56]. groups (p � 0.28) [63].
The open-label extension of the RISE and RIDE pro- The REFINE was a phase III, 12-month, double-
tocols tried to answer the question of whether an intravitreal masked, multicenter, laser-controlled study conducted on
ranibizumab “less-than-monthly injection” regime would be Chinese patients with DME. Patients were randomly
as effective as monthly injection regime [57]. According to assigned (4.1) to receive intravitreal ranibizumab injections
the results of this study, the functional and anatomic out- or laser [64]. The mean BCVA improvement with rani-
comes achieved with monthly ranibizumab might be bizumab at month 12 (+7.9 letters) was statistically sig-
maintained with a reduction in treatment frequency [57]. nificantly greater (p < 0.001) than that observed with laser
The efficacy and safety of ranibizumab and bev- (+2.5 letters) [64].
acizumab were compared directly in a randomized, double- Table 3 summarizes the main results of ranibizumab
masked, 36-week, and 3-period crossover study [58]. Pa- observed in different studies included in this review.
tients received monthly intravitreal injections of bev-
acizumab (1.25 mg) or ranibizumab (0.3 mg). The results of (1) Safety. As regards the safety profile, the incidence and
this study found a slightly but statistically significant dif- characteristics of the adverse events were similar to that
ference in BCVA improvement (difference of 1.3 letters in observed with bevacizumab. Systemic VEGF inhibition-
favor of ranibizumab; p � 0.039) and in the mean CMT related adverse events such as stroke and myocardial in-
reduction (difference of 48 μm in favor of ranibizumab; farction have been described with the administration of
p < 0.001) [58]. ranibizumab [45–64]. The most commonly reported ocular
The question of whether early visual acuity response to adverse event among the different studies was conjunctival
ranibizumab in DME patients is associated with long-term hemorrhage. Other ocular side effects included endoph-
outcomes was evaluated in a post hoc analysis of the DRCR. thalmitis, ocular hypertension, and retinal detachment
net Protocol I [59]. The results of this study suggested that a [45–64].
Table 3: Overview of the functional and anatomic results of ranibizumab.

BCVA (ETDRS letters) CRT (µm)
Study Ref. Duration (w) Regimen N (eyes)
Baseline Change Baseline Change
Rani 42 24.85 7.24∗∗ 422 −106.3
READ-2 [43] 24 Rani + laser 42 24.87 3.8 474.5 −117.2
Laser 42 28.35 −0.43 439.6 −82.8
Rani 102 60.2 (9.9) 7.8 (7.7)∗∗ 455.4 (114.2) −194.2 (135.1)∗∗
RESOLVE [44] 52
Sham 49 61.1 (9.0) −0.1 (9.8) 448.9 (102.8) −48.4 (153.4)
Rani + sham 116 N.A. 6.1 (6.3)∗∗ N.A. −118.7 (115.1)∗∗
RESTORE [45] 52 Rani + laser 118 N.A. 5.9 (7.9)∗∗ N.A. −128.3 (114.3)∗∗
Laser + sham 111 N.A. 0.8 (8.6) N.A. −61.3 (132.3)
Rani + sham 116 N.A. 8.0 (1.1) 116 −142.1
Ext.
RESTORE [55] 156 Rani + laser 118 N.A. 6.7 (1.1) 118 −145.9
Laser + sham 111 N.A. 6.0 (1.1) 111 −142.7
Rani 0.5 113 68 (56–−75) +2 (−3 to +7)∗∗ 352 (283–−476) −26 (−92 to +15)∗
DRCR.net [47] 56 Triam 109 67 (59–−75) +1 (−3 to +8)∗∗ 359 (271–−472) −75 (−168 to −17)∗∗
Sham 123 67 (52–−75) −2 (−8 to +3) 355 (285–−510) 0 (−80 to +70)
∗∗∗
Rani 0.3 mg 125 54.7 (12.6) 12.5 4745. (174.8) −250.6∗∗∗
RISE [46] 104 Rani 0.5 mg 125 56.9 (11.6) 11.9∗∗∗ 463.8 (144.0) −253.1∗∗∗
Sham 127 57.2 (11.1) 2.6 467.3 (152.0) −133.4
Rani 0.3 mg 125 57.5 (11.6) 10.9∗∗∗ 482.6 (149.3) −259.8∗∗∗
RIDE [46] 104 Rani 0.5 mg 127 56.9 (11.8) 12.0∗∗∗ 463.8 (175.5) −270.7∗∗∗
Sham 130 57.3 (11.2) 2.3 447.4 (154.4) −125.8
Rani 0.3 mg 125 54.7 (12.6) 14.2 (12.8)∗∗∗ 4745. (174.8) −261.2 (196.5)
RISE [49] 156 Rani 0.5 mg 125 56.9 (11.6) 11.0 (12.9)∗∗∗ 463.8 (144.0) −269.1 (178.9)
Sham 127 57.2 (11.1) 4.3 (14.9) 467.3 (152.0) −200.1 (215.6)
Rani 0.3 mg 125 57.5 (11.6) 10.6 (12.9)∗∗∗ 482.6 (149.3) −261.8 (180.8)
RIDE [49] 156 Rani 0.5 mg 127 56.9 (11.8) 11.4 (16.3)∗∗∗ 463.8 (175.5) −266.7 (207.8)
Sham 130 57.3 (11.2) 4.7 (13.3) 447.4 (154.4) −213.2 (193.5)
Rani 0.3 mg 89 54.4 (12.0) −1.7 (−3.6 to 0.2) 475.9 (170.2) 23.3 (−7.7 to 54.3)
RISE [57] 208 Rani 0.5 mg 79 56.5 (10.9) 0.8 (−1.1 to 2.7 476.7 (139.5) 4.2 (−17.1 to 25.4)
Sham 77 57.8 (10.5) 1.3 (−0.3 to 2.9) 462.8 (141.4) 29.6 (3.4–55.7)
Rani 0.3 mg 83 58.3 (11.3) −0.9 (−3.6 to 1.8) 480.3 (186.9) 46.1 (−2.6 to 94.8
RIDE [57] 208 Rani 0.5 mg 84 56.9 (11.8) 0.6 (−1.2 to 2.4 481.1 (163.2) 44.1 (16.1–72.1)
Sham 88 57.8 (11.4) −2.6 (−5.6 to 0.5) 441.3 (146.3) 9.6 (−18.4 to 37.6)
Rani 0.5 mg 307 59.6 (10.5) 7.8 (0.7)∗∗ 473.4 (166.1) −146.5 (157.6)∗∗
REFINE [64] 52
Laser 77 58.2 (9.4) 2.5 (7.8) 475.0 (161.5) −85.9 (166.6)
Note. READ-2: measured subfoveal thickness. RESOLVE: ranibizumab group included intravitreal injections of 0.3 mg and 0.5 mg (51 eyes each). DRCR.net:
patients received laser besides their treatment assigned; measured central subfield thickness; differences were calculated at week 14 (primary outcome of the
study). RESTORE extension: all patients enrolled in the extension study were eligible to receive intravitreal ranibizumab 0.5 mg injections (subgroups were
maintained for evaluating the effect of ranibizumab according to the initial treatment). ∗ p < 0.01 vs. reference comparator (laser, sham, triamcinolone, etc.).
∗∗
p < 0.001 vs. reference comparator (laser, sham, triamcinolone, etc.). ∗∗∗ p < 0.0001 vs. reference comparator (laser, sham, triamcinolone, etc.). w: weeks;
BCVA: best-corrected visual acuity; EDTRS: Early Treatment of Diabetic Retinopathy Study; CRT: central retina thickness; DRCR.net: Diabetic Retinopathy
Clinical Research Network; Rani: ranibizumab; Triam: triamcinolone acetonide.
Repeated intravitreal ranibizumab injections may in- NY, USA) is a fusion protein (115 kDa) comprising the second
crease the risk of ocular hypertension [65]. According to the Ig domain of human VEGFR1, the third Ig domain of human
results of the DRCR.net study, repeated intravitreal injec- VEGFR2, and the Fc region of a human IgG1 [67–69].
tions of ranibizumab were associated with a greater prob- The first high-quality scientific evidence published about
ability of sustained intraocular pressure (IOP) elevation than the role of aflibercept in the management of DME were the
laser treatment (hazard ratio 2.9, p � 0.01) [65]. VIVID in Europe [70] and the VISTA in the United States [71].
Regarding the potential negative effect on corneal endo- VIVID and VISTA were two similarly designed ran-
thelium of ranibizumab or bevacizumab, monthly intravitreal domized phase III trials that compared the efficacy and
0.5 ranibizumab or 1.25 mg bevacizumab during three months safety of two doses of intravitreal regimes of aflibercept vs.
did not show any negative effect on corneal endothelium [66]. laser for DME treatment [70, 71]. After a monthly loading
dose of 5 injections, aflibercept 2 mg was administered every
4 (IA4W) or every 8 weeks (IA8W) [70, 71]. After 100 weeks
of follow-up, the proportion of patients achieving a BCVA
®
3.1.4. Aflibercept. Aflibercept (EYLEA ; Bayer HealthCare,
Berlin, Germany/Regeneron Pharmaceuticals Inc., Tarrytown, improvement of ≥15 letters in VIVID was 38.2%, 31.1%, and
12.1% for the IA4W, IA8W, and laser treatment regimes, greater than that obtained with bevacizumab and ranibi-
respectively (p < 0.0001), and in VISTA was 38.3%, 33.1%, zumab at 1 year. However, at 2 years, aflibercept was only
and 13.0% for the IA4W, IA8W, and laser treatment re- superior, in terms of BCVA improvement, to bevacizumab
gimes, respectively (p < 0.0001). The pooled mean BCVA [75]. Regarding retinal thickness, in eyes with baseline visual
improvement from baseline to week 100 was 10.7 and 10.3 acuity <20/50, reduction observed at 1 year with bev-
for IA4W and IA8W, respectively. There were no significant acizumab was lower than with the other anti-VEGF drugs,
differences in terms of BCVA improvement between IA4W but at 2 years the differences had diminished [75].
and IA8W regimes [70, 71]. A secondary analysis of the Protocol T compared
Based on these results, the European Medicines Agency changes in diabetic retinopathy severity during aflibercept,
(EMA), in 2014, and the Food and Drug Administration bevacizumab, or ranibizumab treatment for DME [76]. At 1
(FDA), in 2015, approved the use of aflibercept for treating year, in eyes with no proliferative diabetic retinopathy, a
DME. FDA approved a dose of 2 mg per injection (5 significantly greater proportion of patients treated with
monthly injections as loading dose plus bimonthly injections aflibercept or ranibizumab had improvement in diabetic
thereafter), while EMA adds (to the aforementioned) the retinopathy severity as compared with bevacizumab
option to establish an incremental extension of intertreat- (p � 0.004 for aflibercept vs. bevacizumab and p � 0.01 for
ment intervals after the first year of treatment [6]. ranibizumab vs. bevacizumab), but there was no difference
A post hoc analysis of the VIVID and VISTA trials between aflibercept vs. ranibizumab (p � 0.51) [76]. How-
compared the effect of intravitreal aflibercept on functional ever, at 2 years, no treatment group differences were
and anatomic outcomes in DME patients with and without identified in the proportion of patients who had diabetic
prior anti-VEGF treatment [72]. Mean BCVA improvement retinopathy improvement. As regards the eyes with diabetic
at week 100 in those eyes that did not receive previous anti- retinopathy, at 1 year a significantly greater proportion of
VEGF treatment was 12.0, 11.3, and +2.1 letters for the patients treated with aflibercept had improvement in dia-
IA4W, IA8W, and laser treatment regimes, respectively. In betic retinopathy severity as compared with bevacizumab
previously treated eyes, mean BCVA improvements at week (p < 0.001) or ranibizumab (p � 0.02), but not between
100 were +10.9, +10.8, and −0.8 letters. At week 100, mean ranibizumab and bevacizumab (p � 0.09) [76].
CMT reductions in previously treated eyes were 180.1 μm, Unlike eyes with no proliferative diabetic retinopathy,
196.4 μm, and 94.1 μm for the IA4W, IA8W, and laser these rates and treatment group differences seemed to be
treatment regimes, respectively. In eyes without previous maintained at 2 years [76].
anti-VEGF treatment, at week 100, mean CMT reductions The 2-year outcomes of the ENDURANCE extension
were 200.0 μm, 186.7 μm, and 76.9 μm for the IA4W, IA8W, study found that the number of intravitreal aflibercept in-
and laser treatment regimes, respectively [72]. Functional jections was substantially reduced in the fourth and fifth
and anatomic improvements were statistically significant years of aflibercept dosing following initiation of therapy in
with both intravitreal aflibercept regimes as compared with the VISTA DME trial [77]. BCVA improvements achieved
laser. There were no statistically significant differences in during the 3-year VISTA trial were maintained [77].
both functional and anatomic outcomes between the two An additional post hoc analysis of the Protocol T
intravitreal aflibercept regimes [72]. evaluated the proportion of eyes with persistent DME after
The ENDURANCE extension study was a phase IV, 24 weeks of treatment with aflibercept, bevacizumab, or
open-label study conducted on patients who completed the ranibizumab. Persistent DME through 24 weeks was sig-
VIVID and VISTA DME trials [73]. During the ENDUR- nificantly less frequent with aflibercept than with the other
ANCE study, both interval between patient visits and treatments (p < 0.001 vs. bevacizumab and p � 0.05 vs.
intravitreal aflibercept injections were tailored according to ranibizumab) and less frequent with ranibizumab than with
the patient’s needs [73]. Sixty patients were enrolled in the bevacizumab (p < 0.001) [78]. Although the proportion of
ENDURANCE study. The BCVA improvements achieved eyes with persistent DME was significantly lower with
during the VISTA were maintained and stable (<1.5 letters) aflibercept, 31.6% of the eyes (60/190) did not adequately
over the 12-month follow-up. respond to this treatment [78].
Similar to BCVA, mean CMT remained relatively stable An integrated post hoc subanalysis of the two phase II
during the ENDURANCE study [73]. Regarding treatment trials VISTA and VIVID assessed the effect of baseline
needs, 42 (70%) received ≥ 1 intravitreal injection of afli- factors on differences in BCVA improvement with intra-
bercept (mean 4.5 injections), without any significant impact vitreal aflibercept injection vs. laser in DME patients [79].
of the treatment received during the VISTA [73]. According to the results of this study, BCVA improvement
The results of the 148-week analysis from the VISTA and was significantly greater with aflibercept than with laser and
VIVID studies confirmed the previous findings [74]. BCVA was not influenced by any baseline factor [79].
improvements achieved with both intravitreal aflibercept The Protocol V was a prospective and randomized
regimes at week 52 and week 100 were maintained at week clinical trial that compared three different strategies for
148. As regards the safety profile, the findings were con- treating eyes with DME and good visual acuity (20/25 or
sistent with the previous reports [70–73]. better) [80]. Study eyes were randomly assigned in a 1 : 1 : 1
A post hoc analysis of Protocol T found that, for those ratio to 2.0 mg of aflibercept, focal/grid laser photocoagu-
eyes with a baseline visual acuity <69 letters, the BCVA lation, or observation. In the laser photocoagulation and
improvement achieved with aflibercept was statistically observation groups, it was allowed to start with aflibercept if
visual acuity met specific worsening criteria. At 2 years, there for the BCVA and CMT, respectively) [88]. Nevertheless, the
were no significant differences in the proportion of eyes with number of intravitreal injections of conbercept was signif-
at least a 5-letter visual acuity decrease (aflibercept vs. laser, icantly lower with the combined therapy (3.3 ± 1.2 per eye)
p � 0.79; aflibercept vs. observation, p � 0.79; and laser vs. than with conbercept alone (5.6 ± 0.8 per eye), p < 0.001 [88].
observation, p � 0.79). In other words, in eyes with DME and The efficacy of intravitreal conbercept and ranibizumab
good visual acuity, aflibercept or laser photocoagulation for treating DME was evaluated in a 12-month, retrospec-
appeared to be no superior to observation [80]. tive, and real-life study [89]. Patients received intravitreal
The real-world functional and anatomic outcomes of conbercept injections or intravitreal ranibizumab injections,
intravitreal aflibercept in DME patients, either naı̈ve or once a month for 3 months followed by as-needed therapy.
previously treated, were assessed in a prospective, obser- At month 12, BCVA improvement was 9.3 ± 5.2 and 8.9 ± 4.4
vational, and multicenter cohort study conducted in France in the conbercept and ranibizumab groups, respectively,
[81]. The APOLLON evaluated, as the primary outcome, the p < 0.001 each (with no significant differences between
mean change in BCVA from baseline to month 12. The study groups, p � 0.756). At month 12, the mean CMT reduction
included 147 patients (77 treatment-naı̈ve and 70 previously was 138.4 ± 97.7 μm in the conbercept group and
treated) followed up for at least 12 months. The mean 145.2 ± 72.5 μm in the ranibizumab group, p < 0.001 each
improvement in BCVA at month 12 was 7.8 ± 12.3 and (with no significant differences between groups, p � 0.748)
5.0 ± 11.3 letters in treatment-naı̈ve and previously treated [89].
patients, respectively, p � 0.1541 (independent-sample Stu- The efficacy and safety of intravitreal conbercept for the
dent’s t-test) [81]. Intravitreal aflibercept significantly retreatment of DME were evaluated in a retrospective study.
duced CMT in both groups, without differences between The BCVA improvement at months 1 and 3 was sadistically
them. The mean intravitreal injection administered during significant; however, such improvement started to decrease
the study was 7.6 ± 2.5 in the treatment-naı̈ve group and at month 6 [90]. Notably, 32.6% of the eyes treated with
7.6 ± 2.3 in the previously treated one, p � 1.000 (indepen- intravitreal conbercept were not sensitive to it within half a
dent-sample Student’s t-test) [81]. year. CMT reduction was basically maintained at month 12
Table 4 summarizes the main results of ranibizumab [90].
observed in different studies included in this review. Moreover, a meta-analysis that compared the efficacy of
conbercept and ranibizumab for the treatment of DME
(1) Safety. The incidence of either ocular or systemic side reported that intravitreal conbercept was significantly su-
effects did not significantly differ from those reported for perior to ranibizumab in terms of CMT reduction, but no
bevacizumab or ranibizumab [35, 36, 70–81]. statistically significant difference with regard to visual im-
Ziv-aflibercept (Zaltrap, Sanofi-Aventis US, LLC, provement [91].
Bridgewater, New Jersey, USA, and Regeneron Pharma- Additionally, it appears that conbercept was able to
ceuticals, Inc., Tarrytown, New York, USA), a recombinant significantly improve the BCVA independently of the
fusion protein, has a mechanism that is similar in action to baseline visual acuity, although for worse baseline visual
that of aflibercept and is available at a lower cost than the acuity (20/50 or worse), BCVA improvement was more
proprietary anti-vascular endothelial growth factor (VEGF) prominent than that of better baseline visual acuity (20/32 to
drug [82, 83]. 20/40) subgroup [92].
The results of a 3-month prospective study, which in- The results of a meta-analysis, which included 588 pa-
cluded 17 eyes with DME, found that off-label use of tients, compared the effect and safety of conbercept and
intravitreal ziv-aflibercept improved visual acuity, without ranibizumab in the treatment of DME suggested that
detectable ocular toxicity or systemic side effects in DME intravitreal injections of conbercept were superior to rani-
[84]. bizumab in both reducing CRT and improving BCVA [93].
Additionally, the results of a retrospective study that Regarding safety, the pooled results showed that there was
evaluated the clinical outcomes and safety profile of ziv- no significant difference in the risk of intraocular pressure
aflibercept in eyes that received ≥10 intravitreal injections increase (or conjunctival hemorrhage between two groups
found that multiple intravitreal injections of ziv-aflibercept [93].vd
were associated with a significant improvement in both
functional and anatomic outcomes, with a good safety (1) Safety. The most frequently reported ocular adverse event
profile [85]. was conjunctival hemorrhage [88–93]. The incidence and
type of adverse events did not significantly differ from those
previously reported for other anti-VEGF therapies (Sections
3.1.5. Conbercept. Conbercept is a recombinant soluble 3.1.2 to 3.1.4).
VEGF receptor decoy [86]. Its affinity for VEGF is 50 times
that of bevacizumab and 30 times that of ranibizumab [87].
A retrospective study compared the efficacy of intra- 3.2. Steroids. Since there is increasing evidence about the
vitreal conbercept either alone or in combination with laser role of inflammation on the pathophysiology of DME,
[88]. The results of this study suggested that both treatment corticosteroids have taken an active role in its treatment
strategies significantly improved BCVA and reduced CMT, [8–11]. Corticosteroid therapy is able to inhibit many of the
without differences between them (p � 0.164 and p � 0.149 processes known to be involved in the progression of DME,
Table 4: Overview of the functional and anatomic results of aflibercept.

Study Ref. Duration (w) Regimen N (eyes)
IA4W 154 58.9 (10.8) 12.5∗∗∗ 485 (157) −185.9∗∗∗
[70] 52 IA8W 151 59.4 (10.9) 10.7∗∗∗ 479 (154) −183.1∗∗∗
Laser 154 59.7 (10.9) 0.2 483 (153) −73.3
IA4W 154 58.9 (10.8) 11.5∗∗∗ 485 (157) −191.4∗∗∗
VISTA [70] 100 IA8W 151 59.4 (10.9) 11.7∗∗ 479 (154) −191.1∗∗
Laser 154 59.7 (10.9) 6.3 483 (153) −83.9
IA4W 154 58.9 (10.8) 10.4∗∗∗ 485 (157) −200.4∗∗∗
[74] 148 IA8W 151 59.4 (10.9) 10.5∗∗∗ 479 (154) −190.1∗∗∗
Laser 154 59.7 (10.9) 1.4 483 (153) −109.8
IA4W 136 60.8 (10.7) 10.5∗∗∗ 502 (144) −195.0∗∗∗
[70] 52 IA8W 135 58.8 (11.2) 10.7∗∗∗ 518 (147) −192.4∗∗∗
Laser 132 60.8 (10.6) 1.2 540 (152) −66.2
IA4W 136 60.8 (10.7) 11.8∗∗ 502 (144) 211.8∗∗∗
VIVID [70] 100 IA8W 135 58.8 (11.2) 10.6∗∗ 518 (147) −195.8∗∗∗
Laser 132 60.8 (10.6) 5.5 540 (152) −85.7
IA4W 136 60.8 (10.7) 10.3∗∗∗ 502 (144) 215.2∗∗∗
[74] 148 IA8W 135 58.8 (11.2) 11.7∗∗∗ 518 (147) −202.8∗∗∗
Laser 132 60.8 (10.6) 1.6 540 (152) −122.6
IA4W 226 85.2 (3.5) 0.9 (6.4) 306 (55) −48 (65)
Baker et al [80] 104 Laser 240 85.2 (3.8) 0.1 (6.3) 314 (52) −41 (75)
Observation 236 85.2 (3.8) −0.4 (6.4) 314 (64) −42 (75)
Note. ∗ p < 0.01 vs. laser. ∗∗ p < 0.001 vs. laser. ∗∗∗ p < 0.0001 vs. laser. Baker et al. measured central subfoveal thickness. w: weeks; BCVA: best-corrected visual
acuity; EDTRS: Early Treatment of Diabetic Retinopathy Study; CRT: central retina thickness; IA4W: intravitreal injections of aflibercept every 4 weeks;
IA8W: intravitreal injections of aflibercept every 8 weeks.
through anti-inflammatory properties [94] and VEGF in- 12.3% in the 700 µg DEX, 350 µg DEX, and controls, re-
hibition [95]. Corticosteroids stabilize retinal capillaries and spectively (700 µg DEX vs. controls, p � 0.007) [101].
tend to reduce their permeability decreasing the leakage of Additionally, better anatomic outcomes were observed
plasma proteins into the interstitial tissue compartment with the 700 µg DEX than in the control group (p � 0.03).
[8, 9, 96]. However, at month 6, there were no significant differences
Although a single-dose preparation of preservative-free between groups [101]. According to the results of this clinical
®
triamcinolone acetonide (Triesence ; Alcon Laboratories,
Inc., Fort Worth, TX, USA) has been approved by the FDA
trial, 700 µg DEX was an effective option for treating per-
sistent DME, but its effects seemed to be time-limited [101].
to enhance visualization of the vitreous during pars plana The CHAMPLAIN was a prospective, multicenter, open-
vitrectomy and to treat some posterior segment inflam- label, and 26-week study that evaluated the efficacy and
matory diseases [97], it has not been approved for the safety of a 700 µg DEX for the treatment of DME in
treatment of DME. That is why triamcinolone acetonide vitrectomized eyes [102]. At week 26, 700 µg DEX signifi-
would not be analyzed in this review. cantly reduced the mean CMT (p � 0.004) and significantly
improved the mean BCVA (p � 0.046) as compared to
baseline. At week 8, the proportion of eyes that achieved a
3.2.1. Dexamethasone Sustained-Release Implants. BCVA of ≥10 letters were 30.4% [102]. The most commonly
Dexamethasone intravitreal (DEX) implant (0.7 mg) reported ocular adverse events were conjunctival hemor-
(Ozurdex, Allergan, Inc., Irvine, CA, USA) consists of mi- rhage, conjunctival hyperemia, elevation of IOP, and eye
cronized dexamethasone in a biodegradable copolymer of pain [102].
polylactic-co-glycolic acid which slowly releases steroids The PLACID study was a multicenter, prospective,
into the vitreous over a period of about 6 months [98, 99]. In randomized, controlled, double-masked, parallel-group, and
2014, based on the results of the MEAD study [100], the FDA 12-month clinical trial that compared the 0.7 mg DEX
and most European countries approved Ozurdex for the implant (Ozurdex®) in combination with laser therapy vs.
treatment of DME. laser alone for the treatment of diffuse DME [103]. A total of
The first prospective, randomized, and controlled trial 253 DME patients were randomly assigned to 0.7 mg
evaluating the efficacy and safety of an intravitreal DEX in DEX + laser (at month 1) or sham implant + laser. Patients
eyes with DME was published in 2010 [101]. Eyes with could receive up to 3 additional laser treatments and 1
persistent DME (≥90 days of duration) were randomly additional DEX implant or sham treatment as needed [103].
assigned to receive a DEX implant (700 µg or 350 µg) or The proportion of eyes with a BCVA improvement of ≥10
observation. At month 3, the proportion of eyes achieving a letters was significantly greater at months 1 and 9 in the
BCVA improvement of ≥10 letters was 33.3%, 21.1%, and combination group than in the laser group (p < 0.001 and
p � 0.007, respectively), although at month 12 such a dif- and 68 (77%) of the 88 enrolled eyes completed the 24-
ference was not significant [103]. Additionally, the area of month trial [105]. The results of the BEVORDEX study at 2
vascular leakage was significantly decreased in the combi- years found that 43% (20/46) DEX and 45% (19/42) bev-
nation group as compared with the laser group (p � 0.041). acizumab-treated eyes achieved a BCVA improvement of
Regarding safety, the incidence of elevation of IOP was ≥ 10 letters (p � 0.99) (105). At month 24, there were sig-
significantly greater in the combination therapy group than nificant differences between groups in the mean CMT re-
in the laser group, but no eyes in the combination group duction. Although, during the second year, the mean
required glaucoma surgery. Cataract-related side effects number of intravitreal injections with bevacizumab
were more frequent in the combination group (22.2%) than (4.8 ± 5.1) was greater than that of DEX (2.2 ± 1.2), the
in the laser group (9.5%), although there was no difference in difference was less pronounced than during the first year
the number of cataract surgeries between groups (4 eyes in [104, 105].
the combination group and 5 eyes in the laser alone group) The efficacy and safety of DEX implant in DME eyes that
[103]. did not adequately respond to three monthly intravitreal
One of the most important studies assessing the effect of injections of anti-VEGF were evaluated in a prospective
DEX treatment in DME patients was the MEAD [100]. The clinical trial [106]. The results of this study suggested that
MEAD was two prospective, multicenter, randomized, DEX significantly improved BCVA at month 2 (p � 0.0381)
masked, sham-controlled, three-year, and phase III clinical and significantly reduced CMT at months 1, 2, and 3
trials designed to evaluate the efficacy and safety of DEX (p � 0.0343, p � 0.0288, and p � 0.0370, respectively). In the
implant 0.7 and 0.35 mg in patients with DME [100]. At negative side, as compared with baseline, the IOP was
baseline, study patients were randomly assigned (1 : 1 : 1) to significantly greater at months 1, 2, and 3 (p � 0.0003,
receive DEX implant 0.7 mg, DEX implant 0.35 mg, or a p � 0.0003, and p � 0.0048, respectively) [106].
sham procedure. The proportion of patients achieving a The results of the BEVORDEX 12-month study [104]
BCVA improvement of ≥15 letters at year 3 (or at the last were confirmed by a single-center, randomized, and subject-
study visit) was significantly greater with both DEX implant masked study conducted on eyes with persistent DME [107].
0.7 mg (22.2%, p < 0.001 vs. sham) and DEX implant 0.35 mg The results of this study found no differences in the mean
(18.4%, p � 0.018 vs. sham). Interestingly, the treatment change in BCVA between DEX (+5.8 ± 7.6 letters) and
effect was really fast; in fact, significant differences in the bevacizumab (+5.6 ± 6.1) (p � 0.785). Nevertheless, the mean
proportion of eyes gaining ≥15 letters were observed as early change in CMT was significantly greater with DEX
as day 21. The mean CMT reduction was significantly greater (−122 ± 120 μm) than with bevacizumab (−13 ± 105)
with 0.7 mg DEX (−111.6 ± 134.1 μm) and 0.35 mg DEX (p < 0.001). Similarly, in the BEVORDEX 12-month study
(−107.9 ± 135.8 μm) than with sham (−41.9 ± 116.0 μm), (171), the number of injections was significantly greater with
p < 0.001 each [100]. bevacizumab (7.0 ± 0.2) than with DEX (2.7 ± 0.5)
Among phakic eyes at baseline, the incidence of cataract- (p < 0.001) [107].
related side effects was 67.9%, 64.1%, and 20.4% in the 0.7 mg A single-masked, randomized controlled study deter-
DEX, 0.35 mg DEX, and sham, respectively. The rate of mined whether combined therapy with DEX + intravitreal
cataract surgery was 59.2%, 52.3%, and 7.2% in the 0.7 mg bevacizumab (1.25 mg) provides better outcomes than
DEX, 0.35 mg DEX, and sham, respectively. An increase in bevacizumab monotherapy in DME eyes [104]. At month 12,
IOP was observed in 27.7%, 24.8%, and 3.7% of the eyes BCVA improvement was significant and equivalent in both
underwent 0.7 mg DEX, 0.35 mg DEX, and sham, respec- groups (+5.4 and + 4.9 in the combined and bevacizumab
tively. Five (1.4%) eyes in the 0.7 DEX, 3 (0.9) in the 0.35 monotherapy groups, respectively, p � 0.75). Nevertheless,
DEX, and 1 (0.3%) sham required a glaucoma procedure the central subfield thickness reduction was significantly
(trabeculoplasty, iridotomy, iridectomy, or trabeculectomy) greater with the combined therapy than with bevacizumab
[100]. alone (mean difference, 69 μm, 95% confidence
The BEVORDEX study was a phase II, prospective, interval � 9–129; p � 0.03) [108].
multicenter, randomized, single-masked clinical trial that Data collected from the MEAD trials were pooled [109].
compared the 0.7 DEX implant Ozurdex vs. bevacizumab in This post hoc analysis aimed at comparing the long-term
patients with DME [104]. This study enrolled 88 eyes from 61 effects of DEX (either 0.7 mg or 0.35 mg) on the anatomic
patients who were randomized to receive DEX (46 eyes) outcomes. Patients were randomized (1 : 1 : 1) to intravitreal
every 16 weeks or bevacizumab (42 eyes) every 4 weeks, both DEX implant 0.7 mg, DEX implant 0.35 mg, or a sham
PRN. At month 12, the proportion of eyes having a BCVA procedure in the study eye. Of the 1,048 randomized patients
improvement of ≥10 letters was 41 % (19/46) and 40% (17/ of the intend-to-treat population, 607 (57.9%) patients
42) in the DEX and bevacizumab groups, respectively completed all visits. At the end of the study follow-up, the
(p � 0.83). The mean CMT reduction was significantly mean CMT reduction was significantly greater with both 0.7
greater with DEX (187 μm) than with bevacizumab (122 μm), DEX (117 μm) and 0.35 mg DEX (127.8 μm) than with the
p � 0.015. The mean number of intravitreal injections with sham (62.1 μm), (both p < 0.001 vs. sham) [109].
DEX (2.7) was significantly lower than with bevacizumab The UDBASA was a multicenter, prospective, and
(8.6) [104]. randomized study, conducted on patients with DME,
The eyes included in the BEVORDEX study continued in designed to evaluate a single administration vs. a PRN
the trial for another year on the same treatment allocation, administration of a DEX [110]. Patients were randomly
assigned to two groups: In Group I, patients were treated a 15-letter improvement at month 36. Additionally, there
according to the MEAD protocol (only one DEX during the was a significant decrease in CMT at month 36.
6 months of follow-up) [100]; in Group II, patients were A retrospective and multicenter study assessed the ef-
treated on as-needed basis (once received the first DEX, ficacy and safety of repeated DEX, over a 24-month follow-
patients visited every month and based on BCVA and CMT up period, in DME eyes, either naı̈ve or refractory to anti-
receive a customized PRN treatment regime) [110]. As VEGF, in a real setting [118]. The results of this study
compared to baseline, BCVA significantly improved, in both showed that although both, naı̈ve and refractory eyes, im-
groups, at months 1 and 3, and started to decline in Group I proved significantly in vision after 24 months (p < 0.001),
at month 6. Although a difference of 0.11 logMAR in BCVA BCVA improvement was significantly greater in the naı̈ve
between groups was observed (in favor of the PRN regime), eyes that in the refractory ones (p < 0.01.) A statically sig-
it was not statistically significant. A statistically significant nificant CMT reduction was observed in both groups [118].
CMT reduction in both groups was observed up to month 2, When treating DME patients, one important question is
but at that time Group I had begun to revert to pretreatment to know when to change a treatment strategy and what
level. CMT reduction from baseline at months 4 and 5 was treatment to choose. Despite that the anti-VEGF therapy has
statistically significant in favor of the PRN regime (p < 0.05). been chosen as first-line therapy [6], many eyes do not
The mean number of DEX in Group II was 1.6 vs. 1 in Group adequately respond to them. A post hoc analysis of the
I [110]. The proportion of patients with an increased IOP DRCR.net Protocol I revealed that 40% of eyes achieved a
requiring glaucoma medical therapy was 14% and 30% in BCVA improvement <5 letters at week 12 [59]. Additionally,
Groups I and II, respectively (p � 0.13). The need of cataract eyes with a poor response to ranibizumab (those gaining <5
surgery was similar in both groups (48% and 40% in Groups letters after three intravitreal ranibizumab injections ad-
I and II, respectively, p � 0.26 [110]. ministered monthly) usually do not improve further with
A phase II prospective, randomized, and multicenter continuing in ranibizumab treatment [59].
clinical trial compared, in patients with persistent DME, the Moreover, extending the dose to 24 weeks did not
effect of two treatment strategies: continued ranibizumab provide better functional or anatomic outcomes [78].
alone vs. continued ranibizumab plus DEX [111]. DME However, the question of whether patients who do not
pseudophakic eyes with a BCVA score of between 24 and 78 adequately respond to anti-VEGF could benefit from an
letters and previously treated with anti-VEGF therapy (at early change to another therapy has not been fully
least 3 anti-VEGF injections) were included in the study. elucidated.
There was a run-in period, where the patients received A retrospective, multicenter, and case-control study,
treatment with 3 intravitreal injections of ranibizumab. conducted in a real setting, compared the effect of con-
Those eyes that met the inclusion/exclusion criteria after the tinuing with an anti-VEGF therapy or switching to a DEX in
12-week run-in period were randomized (1 : 1) to receive eyes with refractory DME after three initial anti-VEGF
either intravitreal ranibizumab + sham implant or intra- injections [121]. One hundred and ten (72 eyes in the anti-
vitreal ranibizumab + DEX. BCVA improvement was similar VEGF and 38 in the DEX groups) were included in the study.
in both groups (mean difference, 0.5 letters, p � 0.73). The The mean change in BCVA was significantly greater in the
mean CMT reduction was significantly greater in those eyes DEX (+6.1 ± 10.6 letters) than in the anti-VEGF (+0.4 ± 10.8
treated with ranibizumab + DEX than in those who receive letters) group, p � 0.004. The mean CMT reduction was
ranibizumab alone (mean difference, 52 μm; p < 0.001). The significantly greater in the DEX (− 92.8 ± 173.6 µm) than in
incidence of either increased IOP or initiation of glaucoma the anti-VEGF (+18.3 ± 145.9 µm) group, p < 0.001. At
medical therapy was significantly higher in the ranibizu- month 12, the probability of achieving a BCVA improve-
mab + DEX (29%) than in the ranibizumab alone treated ment of ≥10 letters was significantly greater in the DEX than
eyes (0%), p < 0.001 [111]. in the anti-VEGF group (odds ratio, 3.71; 95% confidence
Table 5 summarizes the main results of the DEX implant. interval, 1.19–11.61; p � 0.024) [121].
Besides the good efficacy and safety profile of DEX re- The effect of early (DME eyes receiving 3 or fewer anti-
ported in the clinical trials [100–111], the efficacy and safety VEGF injections before switch) vs. late switch (DME eyes
®
of Ozurdex for the treatment of DME have been recently
evaluated in clinical and real-life studies [113–120]. In
receiving 6 or more anti-VEGF injections before switch) on
BCVA and CMT was compared in a retrospective study
summary, the results of these studies clearly indicated that [122]. As compared to baseline, BCVA significantly im-
®
Ozurdex significantly improved the functional (visual
acuity) and anatomic (retinal thickness) outcomes, not only
proved in the early-switch group at month 24 (p � 0.043) but
did not in the late-switch group (p � 0.8602). The CMT was
in the midterm [113, 114, 119, 120] but also in the long term significantly reduced in both early- and late-switch groups
[115–118], in both naı̈ve and previously treated DME pa- (p � 0.0002 and p � 0.0038, respectively). Nevertheless, the
tients, but naı̈ve eyes consistently fared better proportion of eyes obtaining a CMT reduction ≥10% was
[113–118, 120]. significantly greater in the early-switch group than in the
Malclès et al. [116], in a retrospective and bicentric study, late-switch one (71.0% vs. 47.4%, p � 0.0498). There was no
evaluated the efficacy and safety of DEX in DME patients in difference in the incidence of IOP increase between both
real-life practice over a period of 3 years. The results of this groups [122].
study found a significant improvement in BCVA (9.5 letters These results were partially confirmed by a retrospective
at month 36, p � 0.023), with 25.4% of eyes achieving at least study, which found that, at month 6, the change in central
Table 5: Overview of the functional and anatomic results of dexamethasone intravitreal (DEX) and fluocinolone intravitreal implants.
Study Ref. Duration (m) Regimen N (eyes)
DEX 0.35 mg 351 56.1 (9.9) 18.4%1∗∗∗ 463.0 (157.1) −107.9 (135.8)∗∗∗
MEAD [100] 36 DEX 0.7 mg 347 55.5 (9.7) 22.2%1∗∗ 466.8 (159.5) −111.6 (134.1)∗∗∗
Sham 350 56.9 (8.7) 12.0%1 460.9 (132.6) −41.9 (116.0)
DEX 0.7 mg 46 55.5 (12.5) 7.9 (11.6) 474.3 ± 95.9 −179.0 (88.8)∗∗
[104] 12
Beva 0.5 mg 42 56.3 (11.9) 7.5 (11.0) 503 ± 140.9 −93.0 (131.6)
BEBORDEX
DEX 0.7 mg 46 55.5 (12.5) 6.9 (2.7 to 11.1) 474.3 ± 95.9 N.A.
[105]† 24
Beva 0.5 mg 42 56.3 (11.9) 9.6 (6.9 to 12.3) 503 ± 140.9 N.A.
DEX 0.7 mg 27 59 (12) 5.8 (7.6) 458 (100) −122 (95)∗∗∗
Shah et al [107] 7
Beva 0.5 mg 23 59 (13) 5.6 (6.1) 485 (122) −14 (141)
DEX + Rani 65 63 (12) 2.7 (9.8) 375 (97) −110 (86)∗∗∗
Maturi et al [108] 6
Sham + Rani 64 63 (13) 3.0 (7.1) 396 8122) −62 (97)
IFSR 0.2 µg 375 53.3 (12.7) p � 0.019 460.8 (160.0) p ≤ 0.003
FAME [132] 24 IFSR 0.5 µg 393 52.9 (12.2) p � 0.015 485.1 (173.8) p ≤ 0.003
Sham 185 54.7 (11.3) — 451.3 (152.0) —
IFSR 0.2 µg 165 54.7 (11.7) 2.4 466.6 (152.9) −173.1∗
FAME‡ [133] 36
Sham 72 557. (11.5) 2.3 435.0 (149.1) −115.6
IFSR 0.2 µg 209 52.2 (13.4) 7.6∗∗ 456.2 (165.9) −186.8
FAME‡‡ [133] 36
Sham 112 54.0 (11.5) 1.8 461.8 (153.5) −160.0
Note. p < 0.05 vs. comparator/sham. ∗∗ p < 0.01 vs. comparator/sham. ∗∗∗ p < 0.001 vs. comparator/sham. ∗∗∗∗ p < 0.0001 vs. comparator/sham. 1Proportion
∗
of patients with a ≥ 15-letter improvement in best-corrected visual acuity (BCVA) from baseline at the year 3. †For those eyes that were pseudophakic at
baseline, the mean improvement in BCVA was 8.9 letters (95% confidence interval (CI), 2.0–13.4) for those treated with the dexamethasone (DEX) implant
and 7.7 letters (95% CI, 3.03–14.8) for those treated with bevacizumab; p � 0.77. For the eyes that were phakic at baseline, the mean improvement in BCVA
was 5.8 letters (95% CI, 0.07–11.5) for those treated with the DEX implant and 10.2 letters (95% CI, 7.17–13.3) for those treated with bevacizumab; p � 0.19.
The specific data regarding central retinal thickness of BEVORDEX study at 24 months are not available from the literature [105] and hence are not listed in
this table. Shah et al. [107] measured central subfoveal thickness. Maturi et al. [108] measured central subfoveal thickness. FAME: The specific data regarding
BCVA and central retinal thickness are not available from the literature [112] and hence are not listed in this table. The p value corresponded to the difference
between intravitreal fluocinolone sustained-release (IFSR) and sham. ‡Nonchronic diabetic macular edema (DME) (<3 years). ‡‡Chronic DME (≥3 years). m:
months; BCVA: best-corrected visual acuity; EDTRS: Early Treatment of Diabetic Retinopathy Study; CRT: central retina thickness; DEX: dexamethasone
implant; Beva: bevacizumab; IFSR: intravitreal fluocinolone sustained-release.
retinal thickness was significantly better in the early-switch management of DME is recommended perioperatively
group than in the late-switch group [123]. [128]. Surgical inflammation associated with cataract sur-
Finally, the results of a retrospective study published gery may be responsible for poor functional outcomes in
recently suggested that, in DME patients who did not ad- DME patients [125–127]. Moreover, diabetic patients have a
equately respond to 3 monthly intravitreal anti-VEGF in- substantial risk of developing DME after cataract surgery
jections, switching to dexamethasone implant provided and particularly in the 3- to 6-month postoperative period
better functional outcomes than those that received >3 anti- [125]. Therefore, the perioperative administration of a DEX
VEGF injections [124]. implant in diabetic patients undergoing cataract surgery
might be beneficial.
(1) DEX Implant in Cataract Surgery. Cataract surgery is a We have evidence suggesting that, in diabetic patients,
common and safe procedure but can be associated with the intraoperative use of a DEX implant in combination
vision-threatening complications in the diabetic population, with phacoemulsification and IOL implantation could
such as diabetic macular edema, postoperative macular provide good functional and anatomic outcomes
edema, diabetic retinopathy progression, and posterior [129–131].
capsular opacification [125, 126]. A prospective study, conducted on 19 eyes of patients
Different hypotheses about the mechanisms involved in the with type 2 diabetes mellitus with DME, who underwent
pathogenesis of cataract in diabetic patients have been pro- cataract surgery, found that intraoperative DEX implant
posed, including polyol pathway, osmotic and oxidative stress, effectively prevented DME worsening after phacoemulsifi-
or autoimmunity [127]. Besides preoperative counselling, which cation [129]. Similarly, Furino et al. [130] reported that
is crucial for diabetic patients, other aspects such as glycemic intraoperative intravitreal DEX provided good functional
control, evidence of ocular inflammation, history of preexisting and anatomic clinical outcomes in DME patients who un-
proliferative diabetic retinopathy, and/or macular edema should derwent cataract surgery and these positive effects last for at
be taken into consideration before cataract surgery in diabetic least 3 months. Moreover, the results of a prospective, single-
patients [125–127]. arm, and open-label study suggested that prophylactic use of
Since preexisting DME can increase the risk of macular intraoperative DEX resulted in excellent anatomic outcomes
edema progression by 20%–50%, an appropriate therapeutic in DME undergoing cataract surgery [131].
A retrospective and comparative cohort study published (27.5%), a greater proportion of eyes with chronic DME
recently compared anatomical and functional outcomes of (42.3%) achieved a BCVA improvement of ≥15 letters [134].
combined phacoemulsification and dexamethasone intra- Elevated IOP was more common in IFSR than in sham
vitreal implant with standard phacoemulsification in pa- control-treated patients. There was no evidence that either
tients with nonproliferative diabetic retinopathy, ME, and glaucoma surgery, laser, or topical medication significantly
cataract [132]. The results of this study found that, in those impacted visual outcomes. None of the previously treated
patients who underwent combined phacoemulsification and eyes with steroids that receive treatment with an IFSR 0.2 μg/
DEX implant, there was a significant and maintained in- day implant required IOP-lowering surgery [135].
crease in BCVA and a significant decrease in central sub- The long-term efficacy and safety of an IFSR were
foveal thickness throughout the study. The IOP significantly assessed in a prospective, randomized, evaluator-masked,
increased during the follow-up in the combined phaco- controlled, and multicenter study. Study patients were
emulsification and DEX implant group, although it randomized (2 : 1) to receive either 0.59 mg IFSR or standard
remained within the normal range. According to the results of care (additional laser or observation) [136]. At 2 years, the
of this study, in diabetic patients with DME, combined proportion of eyes achieving a BCVA improvement ≥3 lines
treatment with phacoemulsification and DEX implant were 31.8% and 9.3% in the IFSR and standard-of-care
provided better functional and anatomic outcomes than groups, respectively, p � 0.0016. However, at 3 years, such
standard phacoemulsification [132]. difference was not statistically significant (p � 0.1566). The
proportion of eyes with no evidence of retinal thickening
was significantly higher in the standard-of-care group than
3.2.2. Fluocinolone Sustained-Release Implants. The efficacy in the IFSR at month 6, and years 1 and 2 (p < 0.0001,
and safety of two intravitreal fluocinolone sustained-release p < 0.0001, and p � 0.016, respectively), but not at year 3
(IFSR) devices 0.2 μg/day (low-dose) or 0.5 μg/day (high- (p � 0.861). An IOP ≥30 mmHg (at any time point visit) was
dose) were assessed in DME patients. Two parallel, pro- observed in 61.4% and 5.8% of the IFSR and standard-of-
spective, randomized, sham injection-controlled, double- care groups, respectively. 33.8% of the eyes treated with IFSR
masked, multicenter clinical trials (FAME trials) were con- required surgery for ocular hypertension by 4 years [136].
ducted on patients with persistent DME who received at least The approved dose for the fluocinolone acetonide im-
1 macular laser treatment. Study subjects were randomized plant (Iluvien®; Alimera Sciences, Inc., Alpharetta, GA,
(2.2 : 1) to low-dose implant, high-dose implant, or sham USA) was 0.19 mg. In theory, it is delivered over 36 months
implant, respectively [112]. At month 24, the proportion of at a rate of 0.2 μg/day [137]. However, pharmacokinetic
patients achieving a BCVA improvement of ≥15 letters was studies reported that IFSR provides sustained delivery for
significantly greater in both low-and high-dose groups than in approximately one year [138].
the sham group (p � 0.002 each). Mean BCVA improvement To date, there have been numerous papers looking at the
was 4.4, 5.4, and 1.7 in the low-dose, high-dose, and sham real-world efficacy and safety profile of the IFSR implant at
groups, respectively (low-dose vs. sham, p � 0.02, and high- years 1 and 2 and data are emerging for 3 years. The results of
dose vs. sham p � 0.016). As compared with sham, CMT these studies are in the same general direction, indicating
reduction was significantly greater in both low and high dose that, on average, IFSR implant significantly improved BCVA
at all the time points measured. The need of glaucoma surgery and reduced CMT in DME patients [139–148].
was 3.7%, 7.6%, and 0.5% in the low-dose, high-dose, and The ILUVIEN Implant for chronic DiabEtic MAcuLar
sham groups, respectively [112] (Table 5). edema (Retro-IDEAL) was a retrospective study designed
In a subgroup analysis of the FAME trials, the efficacy for assessing the efficacy and safety of an IFSR (0.19 mg) in
and safety of an IFSR 0.2 μg/day or sham in eyes with chronic patients with chronic DME in Germany [143]. The results at
(duration of diagnosis, ≥3 years) and nonchronic (duration month 30 found that, from baseline, BCVA significantly
of diagnosis, <3 years) DME were assessed [133]. At month improved (p < 0.05). Additionally, CMT was significantly
36, proportion of patients gaining ≥15 letters in BCVA was reduced at year 3 (p < 0.001) [144].
significantly greater in chronic DME patients (IFSR 0.2 μg/
day, 34.0% vs. sham, 13.4%; p < 0.001), but not in patients
with nonchronic DME (IFSR 0.2 μg/day, 22.3% vs. sham, 3.3. Emerging Therapies
27.8%; p � 0.275). The greater functional response observed
in the chronic DME eyes was not associated with baseline 3.3.1. Designed Ankyrin Repeat Protein (DARPin).
ocular characteristics, changes in anatomic features, or Designed ankyrin repeat protein (DARPin), which derives
differences in retreatment or ancillary therapies. Duration of from natural ankyrin repeats, is a small, single-domain
DME did not influence the incidence of adverse events [133]. protein that can selectively bind to a target protein with high
A post hoc analysis of the FAME trials evaluated the affinity and specificity [149, 150].
treatment outcomes in phakic eyes who received IFSR Besides their high selectivity and affinity, DARPin
0.2 μg/day implant [134]. At month 36, the proportion of molecules also display remarkable stability that confer some
eyes achieving a BCVA improvement of ≥15 letters was advantages over currently available antibodies or antibody
slightly higher in the eyes that had cataract surgery after fragments as potential therapeutics. In addition, DARPin
(35.1%) than in the eyes that had cataract surgery before molecules can be specifically designed to modulate local or
(29.3%). Additionally, as compared with nonchronic DME systemic pharmacokinetics [150, 151].
Abicipar pegol (AGN-150998, MP0112, abicipar; aflibercept 2 mg on a functional and morphological level as
Allergan plc/Molecular Partners) is an antagonist of VEGF- well as durability effect over 2 years [161]. However, its
A characterized by small size, high potency, and long results have not been published yet.
intravitreal half-life [15, 152]. A phase I/II, open-label,
multicenter dose-escalation trial, evaluating the safety and
bioactivity of abicipar pegol in DME patients, found that 3.3.3. Angiopoietin Combination Drugs. Angiopoietins are a
there were prolonged edema reduction and improvement in family of growth factors that bind to endothelial receptor
vision [153]. Similarly, the results from a phase II study tyrosine kinases [162]. Angiopoietin-2 is considered a key
showed that abicipar pegol, injected every 8 or 12 weeks in factor in DME pathogenesis (see Figure 1) [9, 152].
patients affected by DME, offered the functional and ana- As far as we know, there are some ongoing clinical trials
tomical effects with less frequent injections compared with targeting angiopoietins in DME patients [11, 152]. The BOU-
ranibizumab over a 28-week period [154]. LEVARD trial was a prospective, randomized, and multicenter
clinical trial that compared the efficacy and safety and efficacy of
antibody targeting angiopoietin-2 and VEGF-A vs. ranibizu-
mab in patients with DME [163]. The angiopoietin-2 inhibitor
®
3.3.2. Brolucizumab. Brolucizumab (Beovu ) is a low-
molecular-weight, single-chain antibody fragment anti- demonstrated statistically superior VA gains than ranibizumab
VEGF developed by Novartis (Basel, Switzerland) for the at week 24 in treatment-naı̈ve patients [163].
treatment of neovascular age-related macular degeneration,
DME, and macular edema secondary to retinal vein oc- 4. Conclusions
clusion [155].
A 6 mg dose of brolucizumab delivers a molar dose Many different options are currently available for treating
which is about 11 and 22 times higher than aflibercept 2 mg DME. Although laser photocoagulation was considered the
and ranibizumab 0.5 mg, respectively. gold standard treatment for DME for several years, it is not
This drug has been already compared to aflibercept in longer.
patients with neovascular age-related macular degeneration Nowadays, intravitreal corticosteroids and anti-VEGF
[156, 157]. The HAWK and HARRIER, two similarly have become first line for treating DME. The anti-VEGF of
designed phase III clinical trials conducted on patients with choice might depend on baseline BCVA. While aflibercept
neovascular age-related macular degeneration, showed that may be the drug of choice in patients with low baseline
brolucizumab was not inferior to aflibercept in visual BCVA (approximately 20/50 or worse); the three anti-
function at week 48, although anatomic outcomes favored VEGFs (bevacizumab, ranibizumab, and aflibercept) pro-
brolucizumab over aflibercept [157]. Regarding safety, it vide similar functional outcomes in patients with higher
should be mentioned that intraocular inflammation was baseline BCVA (approximately 20/32 to 20/40).
identified in 50 (4.6%) of the brolucizumab-treated patients. Since the identification of the role of inflammation,
Of those, 36 subjects (3.3%) had concomitant retinal vas- corticosteroids have taken an active role in the treatment of
culitis. Of the 36 subjects with intraocular inflammation and DME. Intravitreal corticosteroids represent a valuable option
vasculitis, 23 subjects (2.1%) had concomitant vascular for treating DME. However, they are usually seen as a second
occlusion [157]. The American Society of Retina Specialists choice, particularly in those eyes that have an insufficient
(ASRS) conducted a postapproval analysis of brolucizumab- response to anti-VEGF. Emerging evidence suggests that, in
associated retinal vasculitis after cases [158]. Retinal vas- eyes that did not adequately respond to 3 anti-VEGF injec-
culitis was reported in 26 eyes of 25 patients after treatment tions, switching to a DEX implant provides better functional
with brolucizumab (of which 85% were designated as oc- outcomes than in those who received >3 anti-VEGF injec-
clusive). Twelve eyes (46%) had a greater than 3-line de- tions. This finding brings to the table the convenience of not
crease in VA at the final follow-up, and 12 eyes (46%) had a extending anti-VEGF further in those eyes that exhibited an
final VA of 20/200 or worse [158]. Additionally, a retro- insufficient therapeutic response after three doses.
spective case series found that retinal vasculitis and intra- Since there seems to be a relationship between anti-
ocular inflammation after intravitreal injection of VEGF and vascular disorders, especially in elderly people,
brolucizumab were characterized by variable occlusion of intravitreal corticosteroids would be the treatment of choice
large or small retinal arteries, or both, and perivenular in patients at risk of suffering cardiovascular and/or cere-
abnormalities [159]. brovascular events. Another group of patients who could
However, up to now, there are no published data in DME potentially benefit from corticosteroids as first-line therapy
patients. A 2-year, randomized, double-masked, multicen- are those unwilling to follow the anti-VEGF treatment re-
ter, active controlled study is ongoing to compare the effi- gime (monthly injections and/or monthly visits) during the
cacy and safety of brolucizumab 3 mg and brolucizumab first 6 months. At the time of choosing a corticosteroid,
6 mg vs. aflibercept 2 mg. The estimated study completion dexamethasone should be used first, reserving the use of
date will be October 2021, and its results will be available in fluocinolone for those DME cases that did not adequately
the next few years [160]. respond to other treatments. Intravitreal triamcinolone is
Additionally, the ongoing prospective, randomized, associated with a greater IOP increase and higher incidence
phase III clinical study in DME, KITE, aims to confirm the of cataract, and its use should be reserved in those patients
noninferiority of brolucizumab 6 mg compared to who cannot obtain the approved agents for this indication.
DARPins against VEGF have been demonstrated to [6] U. Schmidt-Erfurth, J. Garcia-Arumi, F. Bandello et al.,
inhibit specifically angiogenesis in both in vitro and in vivo “Guidelines for the management of diabetic macular edema
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athy,” Progress in Retinal and Eye Research, vol. 30, no. 5,
Allergan did not participate in either data analysis or re- pp. 343–358, 2011.
daction of the manuscript. [11] A. I. Arroba and Á. M. Valverde, “Modulation of microglia in
the retina: new insights into diabetic retinopathy,” Acta
Conflicts of Interest Diabetologica, vol. 54, no. 6, pp. 527–533, 2017.
[12] The Diabetic Retinopathy Study Research Group, “Prelim-
Dr. Claudio Furino has received a grant from Allergan inary report on effects of photocoagulation therapy,”
during the conduct of the study. Dr. Francesco Boscia, Dr. American Journal of Ophthalmology, vol. 81, pp. 383–396,
Michele Reibaldi, and Dr. Giovanni Alessio declare that they 1976.
have no conflicts of interest. [13] The Early Treatment Diabetic Retinopathy Study Research
Group, “Photocoagulation for diabetic macular edema: early
treatment diabetic retinopathy study report no. 4,” Inter-
Authors’ Contributions national Ophthalmology Clinics, vol. 27, pp. 265–272, 1987.
[14] D. J. Browning, M. W. Stewart, and C. Lee, “Diabetic macular
All authors met the ICMJE authorship criteria. All authors
edema: evidence-based management,” Indian Journal of
made substantial contributions to conception, design, Ophthalmology, vol. 66, no. 12, pp. 1736–1750, 2018.
analysis, and interpretation of data, contributed to the [15] E. A. Urias, G. A. Urias, F. Monickaraj, P. McGuire, and
writing of the article, provided critical revision of the A. Das, “Novel therapeutic targets in diabetic macular
manuscript, and approved the final version. edema: beyond VEGF,” Vision Research, vol. 139, pp. 221–
227, 2017.
Acknowledgments [16] E. S. Gragoudas, A. P. Adamis, E. T. Cunningham Jr.,
M. Feinsod, and D. R. Guyer, “Pegaptanib for neovascular
Medical writing and Editorial assistant services have been age-related macular degeneration,” New England Journal of
provided by Ciencia y Deporte S.L. and covered by a Grant from Medicine, vol. 351, no. 27, pp. 2805–2816, 2004.
Allergan. Support for this assistance was funded by Allergan, an [17] E. T. Cunningham Jr., A. P. Adamis, M. Altaweel et al.,
AbbVie company. Logistic for writing services has been pro- “Macugen Diabetic Retinopathy Study Group. A phase II
vided by Allergan, an AbbVie company. randomized double-masked trial of pegaptanib, an anti-
vascular endothelial growth factor aptamer, for diabetic
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Hindawi

Claudio Furino ,1 Francesco Boscia ,1 Michele Reibaldi ,2 and Giovanni Alessio 1

Correspondence should be addressed to Claudio Furino; claudiofurino@gmail.com

Academic Editor: Enrique Mencı́a-Gutiérrez

1. Introduction Despite that DME represents a sight-threatening con-

Glutamate Hyperglycemia LDL

ROS Polyol AGEs PKC

Proinflammatory agents PEDF

Activation of microglia + Müllercells + astrocytes Cell apoptosis +

Endothelial cells and pericytes degeneration Blood-retinal barrier dysfunction

(i) Pegaptanib; Bevacizumab; Ranibizumab; Aﬂibercept; Conbercept;

(ii) Steroids (triamcinolone acetonide; dexamethasone; fluocinolone

(iii) Aspirin; nepafenac; bromfenac; diclofenac, and other NSAID

Cytokine and (v) Infliximab; Inhibitors of angiotensin-2; CCR2-CCR5 inhibitor;

Others (vi) Exenatide; lanreotide; IGF-1R blocker; EPO; mecamylamine

Table 1: Overview of the functional and anatomic results of bevacizumab.

Duration N BCVA (ETDRS letters) CRT (µm)

Table 2: Overview of the visual acuity outcomes of the Protocol T.

Table 3: Overview of the functional and anatomic results of ranibizumab.

Table 4: Overview of the functional and anatomic results of aﬂibercept.

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