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n e w e ng l a n d j o u r na l

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edi t or i a l

Treatment Choice for Diabetic Macular Edema

Daniel F. Martin, M.D., and Maureen G. Maguire, Ph.D.
Macular edema is a common cause of vision loss
in patients with diabetes. Chronic elevation of
serum glucose levels leads to capillary damage
that results in microaneurysm formation in the
retina. Leakage from these microaneurysms leads
to vision loss if the fluid involves the center of
the fovea. The mainstay of therapy for more than
25 years was focal laser photocoagulation applied
to or near the microaneurysms.1 However, results
from clinical trials of drugs that block vascular
endothelial growth factor (VEGF) for the treatment of diabetic macular edema have led to a
dramatic shift away from laser therapy to primary
treatment with intravitreal injections of one of
three anti-VEGF drugs: aflibercept, bevacizumab,
and ranibizumab.2,3
Researchers from the Diabetic Retinopathy
Clinical Research Network now report in the
Journal findings from a comparative trial of drugs
to treat diabetic macular edema.4 Although each
of the three drugs produced substantial improvement in visual acuity at 1 year, there were important differences in treatment effects in prespecified subgroups. In eyes with visual acuity
of 20/40 or better, there was no difference among
the drugs in improvement in the visual-acuity
letter score (mean improvement, 8 for each drug)
or the number of injections (median, 9 for each
drug) required to achieve this result. However, in
eyes with visual acuity of 20/50 or worse, there
was a clear advantage with aflibercept in improvement in the visual-acuity letter score (mean improvement, 19) over bevacizumab (mean improvement, 12) or ranibizumab (mean improvement,
14), although the number of injections was
similar among aflibercept (median, 10), bevacizumab (median, 11), and ranibizumab (median, 10).
For the entire study sample, improvement in
the visual-acuity letter score was greater by 2 to

3 with aflibercept than with the other two

agents. However, with a highly significant interaction between baseline visual acuity and treatment effects, the overall results do not apply to
patients in either subgroup.
Aflibercept and ranibizumab reduced retinal
thickness more than bevacizumab in both visualacuity subgroups, but the anatomical benefit
translated into a visual-acuity benefit only in eyes
with a baseline visual acuity of 20/50 or worse.
The greater reduction in retinal thickness with
aflibercept is consistent with the lower rate of
supplemental laser treatment required in aflibercept-treated eyes than in eyes treated with the
other agents.
There were no significant differences in safety
observed among the drugs, although in a post
hoc analysis, there were more cardiovascular
events in patients treated with ranibizumab (37
patients, 17%) than in those treated with aflibercept (20 patients, 9%) or bevacizumab (19 patients, 9%) (P=0.01). Given the absence of differences in cardiovascular safety observed in
other trials of diabetic macular edema, as well
as the absence of consistent differences in cardiovascular safety in comparative trials of these
drugs for the treatment of age-related macular
degeneration,5-9 we agree with the authors that
the difference may have been due to chance and
that the topic warrants continued surveillance.
Approximately 75% of patients with diabetic
macular edema in the general population present
with a visual acuity of 20/40 or better.10 Because
there were no significant differences in safety
or efficacy among drugs in patients with this
presenting visual acuity, cost becomes a major
consideration in choosing therapy. Given the
large difference in cost to patients per dose
among bevacizumab ($50), ranibizumab ($1,200),

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editorial

and aflibercept ($1,950), bevacizumab should be

considered as first-line therapy in patients with
a visual acuity of 20/40 or better.
For patients who present with a visual acuity
of 20/50 or worse, improvement in vision was
greatest with aflibercept and similar between
bevacizumab and ranibizumab. Aflibercept
should be considered as first-line therapy in these
patients, with bevacizumab as the alternative
given the lack of a significant difference in visual
outcome between bevacizumab and ranibizumab
and the large difference in cost between the two
drugs. The equivalence of bevacizumab and ranibizumab in effects on visual acuity has now
been shown in different disease states, including diabetic macular edema in the current trial
and neovascular age-related macular degeneration in several multicenter clinical trials.5-9
There are powerful forces in addition to efficacy and safety that affect drug selection by
physicians. These include the current requirement for a patient-specific prescription, which
limits or delays access to compounded bevacizu
mab in some states; the rebates paid directly to
physicians from pharmaceutical companies to
reward use of a more expensive drug; and the
policy of the Centers for Medicare and Medicaid
Services to reimburse on the basis of a percentage of the cost of a drug, so that the agency
provides higher payments to physicians when
more expensive drugs are prescribed. We believe
that all financial incentives and logistic barriers
to providing the least expensive drug, among
drugs equivalent in safety and efficacy, should be
eliminated so that patients may benefit fully
from the results of this Diabetic Retinopathy
Clinical Research Network trial as well as those
from other comparative trials.

Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.
From the Cleveland Clinic Cole Eye Institute, Cleveland (D.F.M.);
and the Department of Ophthalmology, University of Pennsylvania, Philadelphia (M.G.M.).
This article was published on February 18, 2015, at NEJM.org.
1. Early Treatment Diabetic Retinopathy Study Research Group.

Photocoagulation for diabetic macular edema: Early Treatment

Diabetic Retinopathy Study report number 1. Arch Ophthalmol
1985;103:1796-806.
2. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser
or triamcinolone plus prompt laser for diabetic macular edema.
Ophthalmology 2010;117:1064-77.
3. Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the
da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular
edema. Ophthalmology 2012;119:1658-65.
4. The Diabetic Retinopathy Clinical Research Network.
Aflibercept, bevacizumab, or ranibizumab for diabetic macular
edema. N Engl J Med. DOI: 10.1056/NEJMoa1414264.
5. The CATT Research Group. Ranibizumab and bevacizumab
for neovascular age-related macular degeneration. N Engl J Med
2011;364:1897-908.
6. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative
treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled
trial. Lancet 2013;382:1258-67.
7. Kodjikian L, Souied EH, Mimoun G, et al. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL noninferiority randomized trial.
Ophthalmology 2013;120:2300-9.
8. Krebs I, Schmetterer L, Boltz A, et al. A randomised doublemasked trial comparing the visual outcome after treatment with
ranibizumab or bevacizumab in patients with neovascular agerelated macular degeneration. Br J Ophthalmol 2013;97:266-71.
9. Berg K, Pedersen TR, Sandvik L, Bragadttir R. Comparison
of ranibizumab and bevacizumab for neovascular age-related
macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology 2015;122:146-52.
10. Early Treatment Diabetic Retinopathy Study Research Group.
Focal photocoagulation treatment of diabetic macular edema
relationship of treatment effect to fluorescein angiographic
and other retinal characteristics at baseline: ETDRS report no. 19.
Arch Ophthalmol 1995;113:1144-55.
DOI: 10.1056/NEJMe1500351
Copyright 2015 Massachusetts Medical Society.

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The New England Journal of Medicine

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Copyright 2015 Massachusetts Medical Society. All rights reserved.