Diabetes has been increasing in prevalence over the years, and nearly 30 million Americans
(9.3%) now have diabetes (1). This disease burden on the population also translates
to increased prevalence rates of diabetes complications. Diabetes is associated with
several eye complications, including cataracts and glaucoma (2). However, the most
common eye disorder associated with diabetes is diabetic retinopathy (DR), which is
the leading cause of blindness among U.S. adults (2,3). During the 2005–2008 time
period, >4 million adults ≥40 years of age with diabetes had retinopathy, including
diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), which can
lead to vision loss (1).
The management of systemic disorders is vital to preventing diabetic eye complications
(4). Specifically, the management of diabetes, hypertension, and hyperlipidemia has
been associated with reduced or delayed onset and progression of DR (5–11). However,
even with adequate control of these metabolic conditions, people with diabetes may
still be at risk for developing retinopathy. Adequate eye screening is therefore important
for the early detection and treatment of visual complications (4). Screening recommendations
call for a dilated, comprehensive eye examination within 5 years after diabetes diagnosis
for people with type 1 diabetes and immediately after diagnosis for those with type
2 diabetes (12).
Laser therapy has been the mainstay of treatment for DR and DME. Primarily, laser
photocoagulation treatment has been used to prevent vision loss and to delay progression
of retinopathy (13). The associated adverse effects of laser therapy, including night
and peripheral vision loss, are generally preferred to eventual blindness. When laser
treatment is not feasible, vitreous surgery becomes an option and has been shown to
be beneficial for PDR and DME (4).
Research has supported the intravitreal administration of steroids, whose anti-inflammatory
and antiangiogenic effects are beneficial in the management of PDR and DME. However,
steroid use is also associated with elevated rates of intraocular pressure, cataracts,
glaucoma, and infection (13). In the past decade, elucidation of the role of vascular
endothelial growth factor (VEGF) in the development of PDR and DME has facilitated
the production of anti-VEGF pharmacological agents to reduce angiogenesis and blood-retinal
barrier permeability (4,14). Intravitreal injection of these agents—namely, ranibizumab,
aflibercept, bevacizumab, and pegaptanib—has been studied for the treatment of DR
and DME. However, only ranibizumab and aflibercept are approved by the U.S. Food and
Drug Administration (FDA) for use in the treatment of DME and retinopathy in patients
with DME. This article reviews the efficacy and safety of these four anti-VEGF agents.
A summary of relevant efficacy and safety trials is provided in Table 1.
TABLE 1.
Clinical Efficacy and Safety Trials of Anti-VEGF Agents for DME and DR
Trial
Agent
Treatment Arms
Measurements
Outcomes (for treatment arms, respectively)
RESOLVE (16)
Ranibizumab
Pooled treatment (0.3 and 0.5 mg of ranibizumab), sham
Mean change in BCVA score from baseline to 12 months
+10.3 vs. –1 letters
RIDE (18)
Ranibizumab
0.3 mg of ranibizumab, 0.5 mg of ranibizumab, sham
Percentage of subjects gaining ≥15 letters in BCVA score
33.6, 45.7, and 12.3%
RISE (19)
Ranibizumab
0.3 mg of ranibizumab, 0.5 mg of ranibizumab, sham
Percentage of subjects gaining ≥15 letters in BCVA score
44.8, 39.2, and 18.1%
DA VINCI (23)
Aflibercept
Four aflibercept treatment arms (0.5 mg monthly, 2 mg monthly, 2 mg for three initial
monthly doses and then every 2 months, 2 mg for three initial monthly doses), macular
laser photocoagulation
Mean change in visual acuity and central retinal thickness at 24 weeks
Visual acuity: aflibercept arms ranged from +8.5 to +11.4 letters; macular laser photocoagulation
+2.5 lettersCentral retinal thickness: aflibercept arms ranged from –127.3 to –194.5
μm, macular laser photocoagulation–67.9 μm
VISTA (25)
Aflibercept
2 mg aflibercept injection every 4 weeks or every 8 weeks subsequent to five monthly
initial doses, macular laser treatment at baseline and as needed
Change in BCVA score from baseline to week 52
12.3, 10.6, and 0.1 letters
VIVID (26)
Aflibercept
2 mg aflibercept injection every 4 weeks or every 8 weeks subsequent to five monthly
initial doses, macular laser treatment at baseline and as needed
Change in BCVA score from baseline to week 52
10.5, 10.7, and 1.2 letters
Yaseri et al. (randomized, double-masked, phase 3 trial) (29)
Bevacizumab
Intravitreal bevacizumab or in combination with intravitreal triamcinolone acetonide,
macular laser photocoagulation
Percentage of eyes with visual acuity improvement ≥2 Snellen lines at 12 months
38, 9, and 18%
Mahajan et al. (randomized, prospective study) (30)
Bevacizumab
1.25 mg intravitreal bevacizumab injection, 4 mg intravitreal triamcinolone acetonide
injection, macular grid augmentation
Change in BCVA from baseline to 6 months
Intravitreal bevacizumab from 20/160 at baseline to 20/80; intravitreal triamcinolone
acetonide from 20/125 at baseline to 20/63; macular grid augmentation from 20/100
at baseline to 20/80
BOLT (31)
Bevacizumab
Intravitreal bevacizumab (six weekly for maximum of nine injections in the first 12
months, macular laser therapy, four monthly with a maximum of four treatments in the
first 12 months)
Percentage of subjects gaining ≥10 letters in BCVA as measured by letters in the ETDRS
visual acuity test at 24 months
49 and 7%
Cunningham et al. (randomized, double-masked phase 2 study) (34)
Pegaptanib
Injections of pegaptanib (0.3, 1, or 3 mg), sham
BCVA at week 36
20/50 (0.3 mg pegaptanib) and 20/63 (sham)
Sultan et al. (multicenter, randomized, double-masked, phase 2 study) (35)
Pegaptanib
0.3 mg intravitreal pegaptanib, intravitreal sham injection
Percentage of subjects gaining ≥10 letters in BCVA score
36.8 and 19.7%
Pfizer, Inc. (randomized, double-masked, phase 3 study) (36)
Pegaptanib
0.3 mg intravitreal pegaptanib, intravitreal sham injection
Number of subjects gaining ≥10 letters in visual acuity from baseline to week 24
25/123 participants, 6/120 participants
Diabetes Retinopathy Clinical Research Network (aflibercept, bevacizumab, or ranibizumab
for diabetic macular edema) (40)
Aflibercept, bevacizumab, ranibizumab
Intravitreal injection of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab
0.3 mg every 4 weeks
Mean BCVA change at 1 year
13.3, 9.7, and 11.2 letters
Ranibizumab
Approved in February 2015 for treatment of retinopathy in patients with DME, ranibizumab
is also indicated for treatment of DME alone, neovascular age-related macular degeneration
(AMD), and macular edema following retinal vein occlusion (RVO). It is a recombinant
monoclonal antibody fragment that binds and inhibits VEGF-A (15). Of the four anti-VEGF
agents discussed here, it has been the most thoroughly studied and was the first to
be approved for the treatment of DME and DR.
Several clinical trials have been conducted to assess the safety and efficacy of ranibizumab
in people with DME. In the phase 2 RESOLVE trial (16), 102 participants with type
1 or type 2 diabetes and DME were randomized to three monthly injections of a sham,
0.3 mg ranibizumab, or 0.5 mg ranibizumab followed by additional treatment as needed.
Efficacy was measured using the visual acuity test from the Early Treatment Diabetic
Retinopathy Study (ETDRS) starting at a test distance of 4 meters. The primary outcome
was the mean average change in the best corrected visual acuity (BCVA) score from
baseline (the change in BCVA score from month 1 to month 12). At 1 year, the pooled
ranibizumab-treated group gained 10.3 letters, and the sham group lost 1 letter. Results
from RESOLVE determined ranibizumab to be superior to the sham protocol in improving
vision and found it to be safe, with adverse events comparable between treatment and
sham groups.
In two randomized, double-masked, parallel phase 3 trials known as RIDE and RISE (A
Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema)
(17), 382 and 377 participants, respectively, were randomized to monthly injections
of a sham, 0.3 mg ranibizumab, or 0.5 mg ranibizumab. Results of RIDE and RISE demonstrated
a significantly larger proportion of visual gain in the ranibizumab-treated groups
compared to the sham groups. In RIDE, 33.6% and 45.7% of participants taking the 0.3-
and 0.5-mg ranibizumab treatments, respectively, gained ≥15 letters in their BCVA
score, compared to 12.3% of participants on the sham treatment at month 24 (P <0.0001)
(18). Similarly, in RISE, 44.8% of those using the 0.3-mg ranibizumab treatment and
39.2% of those on the 0.5-mg treatment gained ≥15 letters in their BCVA score compared
to 18.1% of those on the sham treatment (P <0.0001) (19).
Aflibercept
Approved in March 2015 for DR in patients with DME, aflibercept is also indicated
for DME alone (approved in 2014), neovascular AMD, and macular edema following RVO
(20,21). Aflibercept binds with high affinity to all isoforms of VEGF-A, VEGF-B, and
placental growth factor. It was shown in animal studies to hold theoretical advantages
over ranibizumab and bevacizumab (22).
In the DA VINCI (DME and VEGF Trap-Eye: Investigation of Clinical Impact) trial (23),
a randomized, double-masked, phase 2 study, the efficacy of aflibercept was compared
to focal coagulation in eyes with DME. The main outcome measures included mean change
in visual acuity and central retinal thickness (CRT) at 24 weeks. Two hundred and
twenty-one participants were assigned to one of five treatment arms: 0.5 mg aflibercept
monthly, 2 mg aflibercept monthly, 2 mg aflibercept for three initial monthly doses
then every 2 months, 2 mg aflibercept for three initial monthly doses and then as
needed, and macular laser photocoagulation. Patients in all four aflibercept treatment
groups experienced visual acuity benefits ranging from gains of 8.5–11.4 letters compared
to a gain of 2.5 letters in the laser therapy group at week 24 (P ≤0.0085). Mean CRT
reductions in the four aflibercept treatment groups ranged from –127.3 to –194.5 μm
compared with –67.9 μm in the laser treatment group (P = 0.0066).
In two similarly designed, randomized, double-masked phase 3 trials known as the VISTA
and VIVID studies (24–26), the safety and efficacy of two intravitreal aflibercept
dosing regimens were compared to macular laser photocoagulation in people with DME.
Four hundred and thirty-six participants were randomized to either 2-mg aflibercept
injections every 4 weeks, 2-mg aflibercept injections every 8 weeks subsequent to
five monthly initial doses, or macular laser treatment at baseline and as needed.
The primary outcome measure was change from baseline in BCVA score at week 52. Mean
BCVA gains for the two aflibercept injection regimens were 12.5 and 10.7 letters,
respectively, compared to a gain of 0.2 letters with laser treatment (P <0.0001).
Thus, aflibercept was found to be more efficacious than laser photocoagulation in
increasing BCVA scores at week 52.
Bevacizumab
Bevacizumab is a VEGF-specific angiogenesis inhibitor approved in 2004 for first-line
treatment of metastatic colorectal cancer with 5-fluorouracil–based chemotherapy.
In addition, it is indicated for several other cancer treatments such as metastatic
renal cell carcinoma, cervical cancer, and metastatic HER2-negative breast cancer
(27). As a recombinant antibody with VEGF-A blocking activity, it has been used off-label
for DME treatment via compounding of an intravenous formulation (28).
In 2005, a randomized, double-masked, phase 3 trial (29) assessed the efficacy of
bevacizumab by assigning 129 participants with significant DME to one of three treatment
arms: intravitreal bevacizumab (IVB) alone, IVB in combination with intravitreal triamcinolone
acetonide (IVB/IVTA), and macular laser photocoagulation (MPC). The study determined
IVB treatment to be superior to MPC treatment for overall visual acuity, but only
for up to 12 months (P = 0.027). The percentage of eyes with visual acuity improvement
≥2 Snellen lines at 12 months for IVB, IVB/IVTA, and MPC were 38, 9, and 18%, respectively.
In a similar randomized, prospective study (30) with 60 participants, 1.25 mg IVB
injection, 4 mg IVTA, and macular grid augmentation treatments were compared with
follow-up measurements at 1, 3, and 6 months. Results demonstrated clinical benefits
and visual acuity improvements for both IVB and IVTA treatments. The mean BCVA change
was from 20/160 at baseline to 20/80 for IVB and from 20/125 at baseline to 20/63
for IVTA (P <0.05). Macular grid augmentation yielded little improvement, with a change
from 20/100 at baseline to 20/80, which did not reach the level of statistical significance
(P = 1.0).
In the BOLT (Bevacizumab or Laser Therapy study) (31), a randomized, prospective phase
3 trial, 80 people with clinically significant macular edema (CSME) were randomized
to either bevacizumab or macular laser therapy (MLT). Bevacizumab-treated patients
were given six weekly IVB treatments, and the MLT-treated group received four monthly
treatments. The primary outcome measure was the difference in BCVA between arms based
on the ETDRS visual acuity test. The mean BCVA for the bevacizumab group changed from
55.7 at baseline to 64.4 at 24 months. For the MLT group, the mean BCVA changed from
54.6 at baseline to 54.8 at 24 months (P = 0.005). The BOLT study demonstrated significant
improvement in BCVA for CSME patients without advanced macular ischemia and the drug’s
efficacy for long-term use.
Pegaptanib
Pegaptanib, a pegylated oligoribonucleotide approved in 2004 for neovascular AMD,
has high affinity and binding to VEGF-165 (32). It has been investigated and reviewed
in several clinical trials for its efficacy and safety in DME, although it is not
FDA-approved for any diabetic eye complications (33).
A randomized, double-masked phase 2 study (34) assessed the safety and efficacy of
pegaptanib in DME patients. One hundred and seventy-two participants were given injections
of either a sham or pegaptanib 0.3 mg, 1 mg, or 3 mg every 6 weeks for 48 weeks. The
primary efficacy endpoints were maintenance of baseline visual acuity or loses of
<15 letters of visual acuity from baseline to week 54. Results demonstrated that all
three pegaptanib-treated groups had more favorable visual acuity change than the sham-treated
group at week 36. Results also demonstrated an overall gain in visual acuity, as well
as reduced risk of visual acuity loss, in DME patients receiving pegaptanib treatment.
The 0.3-mg dose was found to be the most efficacious, and few serious adverse events
were noted. A larger percentage of participants on the 0.3-mg treatment also gained
≥10 letters in visual acuity than of those receiving the sham treatment (34 vs. 10%,
P = 0.003). However, the study was not powered to identify differences in outcomes
with the different pegaptanib doses, and the safety and efficacy of pegaptanib administration
to both eyes concurrently need further investigation.
The efficacy of pegaptanib for DME was evaluated in a randomized, controlled, double-masked
phase 2/3 study (35). Two hundred and sixty participants with DME were randomized
to receive either 0.3 mg intravitreal pegaptanib or an intravitreal injection of a
sham treatment. At week 54, the study determined a greater gain in visual acuity from
subjects receiving the pegaptanib treatment compared to those receiving the sham.
In the pegaptanib-treated group, 36.8% gained ≥10 letters of visual acuity compared
to 19.7% in the sham-treated group (P = 0.0047). At week 102, the pegaptanib-treated
group gained an average of 6.1 letters compared to 1.3 letters for the sham-treated
group (P <0.01).
Results from a randomized phase 3 study (36,37) determined pegaptanib to be superior
to a sham therapy for improvement in visual acuity. Treatments were given every 6
weeks, and the primary outcome measure was the number of participants with an improvement
from baseline of ≥10 letters in visual acuity at week 24. Twenty-five of 123 subjects
on pegaptanib demonstrated the primary outcome compared to 6 of 120 subjects on the
sham (P = 0.003). A secondary measured outcome of mean change from baseline in visual
acuity was +3.1 and –1.2 for the pegaptanib and sham groups, respectively (P = 0.0006).
Discussion
The common side effects associated with anti-VEGF agents include eye pain, vitreous
floaters, cataract, conjunctival hemorrhage, and increased intraocular pressure (15,21,33,38).
Generally, there is increased risk for endophthalmitis and retinal detachment with
intravitreal injections; thus, patients on these agents should be monitored soon after
injection for blurred vision, eye pain or redness, photophobia, or vision changes
(15,21,33,38,39). Serious but uncommon adverse effects observed with these agents
include arterial thromboembolic events such as nonfatal stroke, nonfatal myocardial
infarction, and vascular death. However, there appear to be no major differences among
the four agents in terms of ocular and cardiovascular adverse effects (40–42). These
agents are contraindicated in patients with ocular or periocular infection, active
ocular inflammation, or hypersensitivity to any of the drug components. After receiving
an injection, patients should expect to wait for ∼60 minutes to be monitored for increased
intraocular pressure and should have an alternate driver available after the procedure
(15,21,33).
In contrast to the safety profiles, which are similar, the recently published 1-year
results of a head-to-head clinical trial by the Diabetic Retinopathy Clinical Research
Network (40) found that aflibercept was superior to ranibizumab and bevacizumab in
DME patients with worse baseline visual acuity. However, aflibercept, ranibizumab,
and bevacizumab were found to be equally efficacious in DME patients with mild baseline
visual acuity loss. A systemic review (43) using an indirect comparison method also
evaluated the effectiveness of aflibercept, ranibizumab, and dexamethasone implant
and reported that aflibercept yielded the greatest improvement in visual acuity. Nevertheless,
more long-term studies are needed to fully appreciate the comparative effectiveness
of these agents. Pegaptanib has been shown to be efficacious in the treatment of DME.
However, it is not widely used or studied because of its lower efficacy. It is important
to note that both pegaptanib and bevacizumab are not FDA-approved to treat DME (44).
Additionally, there is a cost differential between these agents that should be considered
when selecting treatment. The costs per intravitreal injection for aflibercept, ranibizumab,
pegaptanib, and bevacizumab are $1,850, $1,170, $995, and $60, respectively (41,45,46).
Conclusion
The standard of care for management of diabetic eye complications with laser photocoagulation
is useful in slowing progression of DR and reducing vision loss. However, this type
of therapy is limited by adverse side effects and a small effect in improving visual
acuity (4,13). Availability and FDA approval of anti-VEGF agents will undoubtedly
influence treatment approaches for DR and DME (37). The efficacy of anti-VEGF agents
compared to laser therapy supports the likelihood that these agents will be considered
more frequently. The availability of long-term efficacy and safety trials will provide
further clarity on the exact roles these agents should play in the management of patients
with DR and DME.