Webinar: Advances in the treatment of diabetic retinopathy

Webinar: Advances in the treatment of diabetic retinopathy

Neyal Ammary-Risch:
Good afternoon. This is Neyal Ammary-Risch, and
I’m the director of the National Eye Health Education Program,
and I’d like to welcome you to our webinar, Advances in the
Treatment of Diabetic Retinopathy: Paradigm Shift in
Patient Care and Education. Joining me this afternoon are my
esteemed colleagues, Drs. Emily Chew and Judy Kim. Dr. Chew is the deputy director
of the National Eye Institute Division of Epidemiology
and Clinical Applications. Her areas of expertise
include retinal diseases, diabetic retinopathy,
age-related macular degeneration, clinical
trials, epidemiology, and nutrition and vision. Dr. Kim is a professor of
ophthalmology at the Medical College of Wisconsin and has
expertise in vitreoretinal diseases and surgery, diabetic
retinopathy, and age-related macular degeneration. She also serves as a vice-chair
of the Diabetic Retinopathy Clinical Research Network, which
we’ll be hearing more about shortly, and is a member of the
National Eye Health Education Program’s Planning Committee,
which is our advisory board. Diabetic retinopathy is an
important topic because it’s currently the leading cause of
vision loss and blindness in the U.S. among working-age adults. And for the first time in
decades, there are newer, better treatments available. We’ll be discussing what
diabetic retinopathy is, how it affects vision, what we have
learned from past clinical trials in medical therapies, key
findings from the recent trials in the DRCR.net, and what they
mean for clinical practice in patient care. We’ll also be talking about some
free patient education resources to help you talk to patients
about diabetic retinopathy. In case you’re not familiar
with the National Eye Health Education Program, or what I’ll
be referring to as NEHEP moving forward, we’re the education arm
of the National Eye Institute at the U.S. National
Institutes of Health. We’re established to serve as an
extension of NEI’s activities in vision research so that
science-based information can be applied to preserving sight and
preventing blindness. We have several program areas,
which include focuses on diabetic eye disease, glaucoma,
low vision, age-related eye diseases, and special
population outreach. And our goal is to translate eye
and vision research into public and professional
education programs. To help provide the latest
research about diabetic retinopathy, we’ll be sharing
information from the NEI-funded Diabetic Retinopathy Clinical
Research Network, which is the collaborative network of more
than 115 sites, more than 400 physicians throughout
the United States. We’re dedicated to facilitating
multicenter clinical research on diabetic retinopathy,
diabetic macular edema, and associated conditions. Its emphasis is on clinical
trials; however, epidemiologic outcomes and other research
may be supported, as well. So before I pass the
slides onto Emily, I want to set the
stage a little bit. Rates diabetes in
the U.S. are high and as you’ll see here, 29 million
Americans have diabetes, which is close to 10
percent of the population. Eight million people have it and
don’t know it, and an estimated 86 million adults have
prediabetes and one of four of them don’t know. These numbers are high, and as
we all know it’s extremely important for people with
diabetes to control their disease to prevent complications
like diabetic eye disease. Diabetic retinopathy is the most
common type of diabetic eye disease, and it damages the
blood vessels in the retina, the light-sensitive tissue in the
back of the eye. The photos here illustrate what
vision may look like for someone who has advanced diabetic
retinopathy and the black splotches you see there are
from leaking blood vessels. Among U.S. adults
aged 40 and older, diabetic retinopathy is
estimated to nearly double over the next 40 years,
so you’ll see this is a growing public
health problem. And, as this slide shows, the
prevalence is on the rise for all major racial and
ethnic groups in the U.S. We know that diabetes can be
controlled, and there are things people can do to delay the onset
or progression of retinopathy, and I’m going to turn things now
over to Emily, who’s going to provide a more in-depth
interview of the disease. So Emily? Emily Chew: Thank you. Thank you, Neyal, and welcome
everyone. It’s my job first to
explain to you what diabetic retinopathy looks like. I’m going to do this in the next
few slides and show you some of the things that we’ve been done
in the past decades that we’ve done in research and
supported by the NIH. This we’ll call Early Treatment
of Diabetic Retinopathy Study classification has been a
classic standard of treatment that we use for
designing clinical trials. And these are done looking at
fundus photographs which are taken of patients with
diabetic eye disease or diabetic retinopathy. I will now speak a little bit
more about how this happens. There are five pathologic
processes that actually occur. The first is the formation of
micro aneurysms and these are outpouchings of the small
blood vessels in the eye. So that the complications from
diabetes has to do with the very small blood vessels in the eye,
in the kidney, and also in the peripheral nerve. And focusing back on the eye, as
the disease progresses, we have this excessive vascular
permeability, which is clearly the leakage of the
blood vessels. Blood vessels are normally
are like pipes that do not allow anything to leak
through, but with damage and with disease, the
leakage occurs. And with time, these blood
vessels actually occlude or they close, so there’s actually a
lack of blood going to the area that it serves and there’s a
lack of oxygen. And the body somehow kind of
makes up for it by forming new blood vessels that are abnormal,
they can cause hemorrhage and with the contraction of these
new blood vessels, you can get scarring and retinal detachment,
which is really a terrible end stage of diabetic macular
edema, a retinal disease. And here’s the first sign
of the disease. Micro aneurysms. You can see with the arrow,
there’s some red spots there. These are outpouchings of blood
vessels that come and go, and at this point there’s minimal
impact of vision. Patients may be 20/20 and
have no idea they have diabetic retinopathy. However, with the blood vessels
leaking more, it causes the swelling in the center of the
macula, the retina, what we call macular edema, and it’s like the
film in the camera that has to be nice and flat but when
the film is swollen, it doesn’t work very well. And the first signs of that are
those yellow, hard exudates that you can see with the arrow. Those are mainly lipids that
leak out of the blood supply and cause damage to the retina. And this is so-called macular
edema and that’s one of the causes of vision loss, the
swelling of the retina. And this can be treated, and
we’ll speak some more on the treatment. One of the ways for diagnosing
this is with the fluorescein angiography, which is a dye
injected into the arm, and we take rapid
photographs of the eye. On the left, you see pictures of
the normal macula where none of the blood vessels are leaking. However, on the right side of
the macular edema, the swelling in the eye, you see a lot of
white coloration there. That’s from the leakage of
the dye into the macula. And this eye is diseased
and has vision impairment. As the blood vessels occlude, we
actually can look at the retina and recognize this. There are more hemorrhages that
you see a lot more red spots in this photograph on the left, and
on the right you see this sort of sausage-like beading,
so-called venous beading. These are abnormalities that we
recognize as this eye is going to more trouble, and these are
abnormal blood vessels you see, which are pre-existing vessels. We have a name for them called
IRMA, intraretinal microvascular abnormalities, which are not the
true new vessels that we’ll see later, but this is a sign of
very poor control and poor oxygen in that area. So this leads to the more
dreaded cause of vision loss, and that’s the new blood
vessels are proliferative diabetic retinopathy. And here, we see what we call a
high-risk case where new vessels are on the optic nerve, that
yellow round spot you see. And you see a line of
hemorrhage. So this patient is at high risk
for developing vision loss. And if this eye has been
well treated with laser, could do very well. And here, it is a case of the
new vessels that is not on the optic nerve but elsewhere. If you see lasers burn spots are
put in the right photograph and those neovascularizations show
up quite well, so you can see new vessels on the nerve or
elsewhere, but, nevertheless, they can bleed and cause damage
and also can contract and can cause more damage. So the blood vessels can be
quite extensive as you see on the photograph on
the left, what we call advanced
proliferative retinopathy, lots of new blood vessels
shown by the arrows there. In the right, these are
contractions of the scar tissue, in other words abnormal tissues
are being pulled up and contracted into a, perhaps
or—detachment, or it can cause bleeds, and this can be damaging
to the vision. So this is the clinical
classification. I want to talk of the global
burden of diabetic retinopathy and then talk about some of the
clinical trials that were done prior to the DRCR.net Diabetic
Retinopathy Clinical Research network that Judy’s going to
talk about and then finish with the medical therapies that which
are very important for our caring—for helping our patients
with diabetic retinopathy. So as Neyal has said, the burden
of diabetic retinopathy is quite immense. Globally, coming from 35 sites
in which we had 22,000 participants that we’re looking
at in the study, about a third of them actually have
diabetic retinopathy. That’s 93 million
people globally. Seven percent will have this
proliferative disease in new blood vessels that
we talked about. About 7 percent will have
diabetic macular edema, and altogether 10 percent may
have the combination. This we call vision-threatening
diabetic retinopathy, either the swelling of the macular edema or
the new vessels growing. And some of the risk factors
we’ve found, the longer the duration of diabetes, the more
likely you’re going to have diabetic eye disease and also
poor sugar control, poor blood pressure control, and even
control of the blood cholesterol is very important in terms of
keeping the eyes in good shape. So this is a graph of all the
things that we’ve done in the NIH in terms of the
different studies. I’m going to speak from some of
these studies that have been done for a number of years
now in terms of treating diabetic retinopathy. On the top, you’ll see a scale
going from no retinopathy to more severe retinopathy. And each of these individual
studies basically cover that aspect of retinopathy, from the
very mild retinopathy to those with high-risk
proliferative retinopathy. And there are a number of
studies that seem to be part of alphabet soup that I’ll go over
this very, very quickly with you in depth, more in depth. So the standard treatment for
diabetic retinopathy has been laser photocoagulation. Also, surgical intervention when
you have scarring or hemorrhage and the medical therapies, which
are in gray here, will be covered by Judy on this. These are eye disease of that or
rather treatments are delivered right into the eye
with injections. And finally, we’ll talk about
systemic medical therapies, which involve blood sugar
control, blood pressure control, and cholesterol control. The first study that’s been
done with the DRS, the Diabetic Retinopathy Study done in the
70s, which proved that laser photocoagulation can reduce the
risk of severe vision loss, that’s very poor vision on two
occasions four months apart, by 50 percent. And this is revolutional. Before that, patients who have
diabetic eye disease were destined to be blind by five
years and most of them have seeing-eye dogs. And that certainly has
changed dramatically. And this is what it looks like. The lasers are done immediately. After lasers, you see in the
picture on the left. On the right, those are the
laser scars a year later. This patient retains 20/20
vision because of the laser photocoagulation. And this slide shows that the
yellow—that on the untreated part of the DRS, which is a
study we’ve just talked about. Another study, which is called
the Early Treatment Diabetic Retinopathy Study, ETDRS, shows
that this risk of severe vision loss is reduced even
further, by 95 percent. Those—this laser is highly
effective and very important in treating patients with
diabetic retinopathy. We also found in the 80s that
focal treatment using laser to the areas of leakage for macular
edema was also important in reducing the risk of moderate
vision loss by 50 percent. And this is a picture
showing what we did in terms of the study. On the left, were the prior to
laser, you see the yellow spots, those hard exudates that we’re
looking at very pathognomonic or very—representative of macular
edema, but when you see maybe right after laser, those white
spots are the laser burns and four months later, the hard
exudates, yellow spots are gone, and the laser’s barely
visible in this case. So this became the standard of
therapy in 1985, and Judy will tell you some more treatments
that we’ve developed since then, but this still remains a very
important part of our treatment. And for those patients with
scarring and hemorrhage, vitrectomy is an insertion of
these micro-instruments under microscopic examination for
removing this scarring and also the hemorrhage. And here’s the case where the
patient had a lot of scarring. This picture on the left is
before surgery, and post-surgery you can see that the eye is
restored to its normal anatomy. This is all the same, this
patient was severely impaired because of the hemorrhage in the
eye and, again, before and after surgery, you can see that you
can recognize the eye from after the vitrectomy as well
as the scar tissue. So these are the indications of
vitrectomy, which is the very severe end of this disease. We’ll turn our attention at the
medical management, we’re looking at glucose pressure
and lipid management. One of the landmark studies done
in 1980s called the DCCT, Diabetes Control and
Complications Trial for type 1 diabetic patients. These patients could either have
no retinopathy at baseline, the so-called primary prevention
group, versus those who have retinopathy at baseline, the
secondary prevention group. There were randomly assigned
to having very intensive blood sugar control
versus the conventional. So when we did that, we found
that we can separate out their A1c levels, and we wanted to
know whether we could prevent the development of retinopathy
and subsequent progression of retinopathy in those who didn’t
have retinopathy. Those who already have
retinopathy, is it too late? Can we prevent it from
progressing? So with that, we were able to
separate the A1c levels, the intensive group had A1c levels
around seven and whereas both the conventional group around
nine, and as we go further we can see that these are
the results of the study. And those who had no
retinopathy, the primary intervention, you can see that
the yellow represents the progression of retinopathy. The worsening of retinopathy
over time and this over a period of eight years with
the intensive group, the rate is much lower. So, there’s a large, large
treatment effect in reducing the risks of progression in those
patients that had no retinopathy, and that’s also
true in patients who already have retinopathy in their eyes. So, it’s not too late. The horse is not out of the
barn, you can actually still treat when you have retinopathy. You can see that this treatment
effect, that yellow conventional group has a lot more higher rate
of progression of retinopathy versus those who were in
the intensive group. So we found that the reduction
of retinopathy was reduced by as much as 34 to 76 percent. No drug can do that for you, so
the importance of treatment with good glucose control cannot be
underestimated. Photocoagulation reduced by a
third (that’s laser) and the first appearance of any
retinopathie is reduced by a quarter. So these are very significant
findings for patients with diabetic retinopathy. It’s also good for the kidneys. It reduces the risk of kidney
abnormalities as well as neuropathy, the nerves that
enter your hands and feet, and they certainly can be reduced
as well with good control. What is astounding about this
is that this study stopped. The clinical trial stopped. We were able to follow this
patient for another additional 25 years, and with that you can
find that even after that short period of time of tight control,
patients still persistently had effects, beneficial effects 25
years later. Patients had less cataract
surgery, less vitrectomy, less laser, so that this is a very
enduring type of treatment. So that was for type 1. For type 2, we’re able to show
very similar findings in patients done in or
the United Kingdom Perspective Diabetes Study, again done in 1977 to 1994, you
can see that this is a tight control of glycemia and
blood pressure control. Again, we found beneficial
effects in these type 2 diabetics that by having very
good blood sugar control reduced the risk of all microvascular
complications, which is the kidney and the retina. And progression of retinopathy
reduced by 25 percent. And the blood pressure control,
which is 140 versus 180, which is very high for now because in
those days it seem like that was a reasonable thing to do, but
even 140 it seemed to be high in the current treatment. But nevertheless, this amount of
blood pressure control reduced the risk of all the retinopathy
and complications by a significant amount, as well. And interestingly, this
so-called metabolic memory, this legacy effect, the fact that
this persistent effect continues on even 10 years later, the
self-reports of hemorrhage or laser photocoagulation or kidney
failure was reduced by 24 percent, 10 years later after
the clinical trial had stopped. So again, this is a very
enduring type of therapy. We now talk about the Actions of
Control Cardiovascular Risk in Diabetes (ACCORD) study. Again, in type 2 diabetes, and
more currently finishing in 2009, we had three medical
therapies of blood sugar control as well as blood lipid control
and blood pressure control. And we went down the glycemic
control to a very low level of less than 6, and blood pressure
control that you can see is 120 versus 140. And for the cholesterol control,
we looked at Fenofibrate, which was used to see
whether it would improve retinopathy as well or
reduce the risk of progression. You can see here the A1c levels
during the course of study was nicely separated out, so those
in the intensive group have maintained a very good
level of around 6.3 or so. And the standard group was at
least 1 percent higher, so clearly there’s a difference
between the two groups. We went in and did eye exam at
baseline and four years, we did the fundus photographs that I’ve
showed you earlier, we want to look at the progression
according to this. We can find that glycemic
control had an odds ratio of .67, anything that’s less than
one means that it’s actually beneficial and affect 95 percent
confidence interval, they did not include one. So both glycemic control and the
lipid therapy with Fenofibrate were highly significant as you
see by the P values, but blood pressure did not make much
difference, at least going to 120 versus 140 was not
particularly influential in any way. So when we looked at the
intensive glycemic control and the Fenofibrate treatment, you
can see it reduced the risk of retinopathy progression
by about one-third. We had no effect on visual
acuity and, again, no effects on high blood pressure control. And what’s interesting is that
as we went on, we came back at eight years after
the study had finished. Again, we found that
glycemic control persisted. So in just a short period of
time of less than four years of duration of blood sugar control
was able to maintain almost a 50 percent reduction
eight years later. So that is very important
for us to consider for all our patients. The lipid effect went away
because we stopped the Fenofibrate, so the Fenofibrate
may be very important, and further studies are being
done in that arena. So with that, I’m going to just
summarize saying we have very high effective therapies from
evidence-based studies, the medical therapies are extremely
powerful and very durable. The treatments using the
standard laser reduced the risk of severe vision loss
dramatically, and laser treatment remains an important
part of therapy; however, we have many other things to offer
you, and Judy will now tell you the new treatments that we’ve
been working on and thank you very much again. Judy? Judy Kim: Thank you. It is my pleasure to present to
all of you exciting new study results that are changing our
current management of diabetic retinopathy in addition
to what Emily has already nicely gone over. We will review findings from the
three pivotal multicenter clinical trial findings from the
Diabetic Retinopathy Clinical Research Network or DRCR.net for
short. These trials are Protocol
I, T, and S. Some of you may ask
what do these letters I, T, and S stand for. Well, it is actually simple. The DRCR.net clinical trials are
named by alphabet, starting with the letter A. What happens when we run
out of all the alphabets? We now have Protocol AA that is
ongoing, and the Protocol AB is currently being developed. We will go over these three
pivotal studies, and we’ll wrap this portion with a summary what
the paradigm shift is. As we have just heard, for many
decades, laser photocoagulation has been the standard of care
for diabetic retinopathy. For proliferative diabetic
retinopathy, the pan-retinal photocoagulation was the
standard of care based on the Diabetic Retinopathy
Study from the 1970s. And then for diabetic macular
edema, focal grid laser treatment was the standard
of care—based on the Early Treatment Diabetic
Retinopathy from the 1980s. And the lasers are still being
used; however, there have been, in my opinion, two important
discoveries that have aided in changing the paradigm
to the current level. The first in my opinion that has
been very contributing to the improvements of diabetic
retinopathy is the development of Optical Coherence
Tomography or OCT. This is a fundus imaging
capability that allows us to see actually the retina at the
macula here, as seen on this slide, with the amount of
retinal edema, seen as the swelling within the retina, as
well as swelling with the fluid accumulation under the retina. Using this OCT technology, we
can actually measure, quantify, how thick the retina is as well
as see the location of the macular edema. So now that we have this
objective way of documenting the amount and the location of
retinal edema, we can use that in clinical trials to see
whether our therapy is beneficial or not, and also we
use it now in the clinic to monitor the response to therapy. The second innovation that I
think has contributed to our new paradigm shift is the discovery
that vascular endothelial growth factor, or VEGF for short, was
elevated in eyes with active proliferative diabetic
retinopathy and in eyes with diabetic macular edema. VEGF mediates or allows growth
of new blood vessels, and also causes damaged vessels
to leak or has a vascular permeability effect. Since these two things happen in
diabetic retinopathy, new blood vessel growth and leaking
vessels, they were a natural target for therapy for diabetic
retinopathy as well as other retinal vascular diseases. Currently there are three
anti-VEGF drugs that have been developed and are in the market. These are Avastin, otherwise
known as bevacizumab, which is the generic name, Eylea or
aflibercept, and Lucentis, otherwise known as ranibizumab. Since the generic names are
quite a mouthful to say and most of you are more aware and
familiar with the brand names, I’m going to be using brand
names as much as possible in my talk. Laser photocoagulation is
performed in the office, and it is still being used to treat
eyes with diabetic retinopathy. Anti-VEGF agents are injected
into the eye, also performed in the office in the United States,
while it may be performed elsewhere such as a procedure
suite or in an operating room in other parts of the world. The eyes are prepped with
povidone iodine, which is seen as this yellowish change on the
eye, which is an antiseptic to prevent infection in the eye. You also see in this slide that
a lid speculum is inserted, which opens the eyelids wide and
pushes the eyelashes away from the injection side. All these are done in order to
prevent complications such as infection that can occur during
injection of anti-VEGF agents. One of the greatest strengths of
having collaborative network such as DRCR.net is that we have
many investigators and study sites throughout the United
States, and we now even have sites in Canada. Therefore, we can enroll large
number of patients in a short period of time, which gives us
power to the results of the study, and we can do types of
studies that are not possible at a single center. Also, the studies are rigorously
monitored for scientific accuracy and patient safety. Now let’s start with Protocol I. At the time when the study was
designed, focal grid laser photocoagulation was the
standard of care for treating eyes with clinically significant
diabetic macular edema. Also, some small studies
seemed to indicate that steroid injection into the
eye may control the diabetic macular edema. However, steroids have known
side effects, such as pressure of the eye going up or
cataracts developing. And we wanted to find ways to
improve vision more than what laser was able to do. Therefore, an anti-VEGF agent,
such as Lucentis, was tested with or without additional focal
grid laser treatment to see whether that can show
improvement that was not seen with the other two treatments. So in Protocol I, the objective
was to evaluate the safety and accuracy of intravitreal
anti-VEGF treatment in combination with immediate laser
at the baseline or deferred laser and intravitreal cortical
steroid in combination with laser compared with laser alone
in eyes with center-involved diabetic macular edema. Eyes with diabetic macular edema
involving the center of the macula by Optical Coherence
Tomography with center-field thickness of greater than the
abnormal and vision 20/32 or worse were eligible
for the study. Between March of 2007 and
December of 2008, total of 691 subjects with
854 eyes at 52 sites were enrolled in this trial. So what did the study find? At year one, which is seen on
the dotted lines on the 52 week mark, and at two years, which is
circled in red in the slide, the laser alone group or the
steroid plus laser group showed improvement. But only about three letters. In contrast, the Lucentis group,
the anti-VEGF group, with prompt or deferred laser at one year
shown on the dotted line and at two years shown on the circle,
showed even more improvement in vision, and this improvement
was statistically significant. This improvement in vision in
the Lucentis-treated groups with prompt or deferred laser was
carried out even through the five years of the study. And between the two groups,
whether they got laser or the laser was deferred, there was no
difference in final visual acuity at five years. This was not
statistically significant. The interesting thing that was
found during the study was that the median number of injections
continued to decline over the five years such that the number
required to improve vision in the first year was eight or
nine, then this dropped precipitously to only needing
two or three injections, and by year three, median
number was one or two. And in years four
and five of the study, the median number was zero. Over half of the eyes
did not require any additional injections. This is important because
that means if we treat patients aggressively in the beginning,
early on with injections, then we may be able to maintain this
good vision even with less number of injections later on. Now this is in contrast to other
diseases such as age-related macular degeneration that
requires continuous frequent number of injections. So, what has been learned from
Protocol I for diabetic macular edema treatment? We found that intravitreal
anti-VEGF agents such as Lucentis with or deferred laser
is more effective in increasing vision compared to with laser or
steroid with laser in eyes with diabetic macular edema involving
the center macula. Vision benefits from
intravitreal Lucentis was maintained for up to five years
of follow-up, and the number of injections that were required
continued to decline in each year of the study. Therefore, intravitreal
anti-VEGF agents such as Lucentis should be considered
for patients with diabetic macular edema and those
who have decreased vision. And this has helped to define
the paradigm shift and has now become the standard of care for
eyes with diabetic macular edema with decreased vision. What about Protocol T? Well, Protocol T came about
because of couple of issues, and I’m pleased to share with you
the most recent year two data of the study that was published in
June of 2016 in Ophthalmology. Eylea and Lucentis both
are FDA, Food and Drug Administration–approved for
diabetic macular edema treatment and can be used in the eye. However, Avastin was actually
developed for treatment of cancer; therefore, it is not
approved by FDA for use in the eye. But when we put a small aliquot,
0.05 ccs, into the eye, we found that it can have
beneficial effects for diabetic macular edema. So people out in the
community were using it. Also, there is significant
difference in the cost of these medications. Eylea and Lucentis are
expensive, while Avastin is 1/40th of the cost of these two
drugs, and given the issue about medical costs and healthcare
costs rising, this can be an interesting study to
look at that, as well. In Protocol T, we looked at
efficacy and safety of intravitreal Eylea, Avastin, or
Lucentis in eyes with center-involved diabetic macular
edema with vision decrease between 20/32 to 20/320. Six hundred sixty eyes from 89
sites were equally randomized to each of these three groups, and
there was head to head to head comparison, in a
carewise fashion. Injections were given every four
weeks until the eyes were deemed stable. And starting at month-six
visits, laser treatment, focal grid laser treatment
can be administered if macular edema persisted
and was not improving. So, what did the study find? The study found that again, just
like in Protocol I, the number of injections required over two
years continued to decline such that in year one, all three
groups required a median of 9 or 10 injections, while the second
year, the number required was 5 or 6. And the laser treatment that was
required was for the three groups was slightly less in the
Eylea group compared to the Avastin group such that at year
two, there was a statistically significant difference between
the number of laser treatments required between Eylea group and
Avastin, with Avastin group needing more laser, at 64
percent compared to 41 percent. How about the visual outcome? This is for the whole group,
regardless of what the baseline visual acuity was. The study found that all three
groups showed visual acuity improvement, both at year one
with 13, 11, or almost 10 letters, and year two with 13,
12, or 10 letters in each of the Eylea, Lucentis, and Avastin
groups, respectively. Interestingly, when the cohorts
were looked at based on their baseline vision of mild vision
loss, 20/32, 20/40 versus 20/50 or worse, there was a
very interesting finding. It happened that half of the
study eyes had 20/30 to 20/40 vision loss at one year and at
two years of the study, all three drugs improved
the vision to be around 7 to 8 letters to
improvement from the baseline. However, when we looked at eyes
that had more significant vision loss at baseline, 20/50 or
worse, at year one, Eylea seems to be more
superior in improving vision. In fact, almost 19 letters were
improved compared to 14 letters in Lucentis and 11
letters in Avastin. At year two, 18 letters were
improved in Eylea group and 16 letters in the Lucentis
group and 13 letters in the Avastin group. It turns out with this
statistical analysis, at year two, both the Eylea and Lucentis
groups were similar in improving vision, and Eylea was still
better than Avastin in terms of improving vision. So what did we learn from the
Protocol T for managing diabetic macular edema? We found that all three
anti-VEGF agents are excellent, whether they had additional
laser or not in improving vision in eyes with center-involved
diabetic macular edema with vision loss. However, based on the study, it
appears that depending on the initial visual acuity, we may
want to consider different anti-VEGF agents, with Eylea
and/or Lucentis being more superior, for worse
vision at baseline. Finally, let’s go over
DRCR.net Protocol S. This is now for proliferative
diabetic retinopathy, whereas the other two were for
diabetic macular edema. Currently, the treatment for
proliferative diabetic retinopathy is pan-retinal
photocoagulation. However, laser treats
with heat and, therefore, it is thermally destructive. When pan-retinal
photocoagulation is placed around the periphery of the
retina, it can cause visual field defect, side vision loss,
or a night vision decline, or sometimes even central
vision loss with increase in diabetic macular edema. Now, based on the other two
studies that I’ve just talked about, the standard of care for
diabetic macular edema, whether the eye has proliferative
diabetic retinopathy or not, is anti-VEGF as the
first-line treatment. So, what if we treat eyes
with an anti-VEGF agent such as Lucentis for
managing proliferative diabetic retinopathy? In this study, the objective was
to determine if visual acuity outcomes at two years in eyes
with proliferative diabetic retinopathy with or without
concurrent diabetic macular edema that received anti-VEGF
agent therapies such as Lucentis with deferred pan-retinal
photocoagulation are non-inferior to those in eyes
that received prompt pan-retinal photocoagulation therapies. So I underline
“non-inferior” there. The other two studies were
superior end-point studies seeing which agent or which
treatment modality improved the vision more. In this non-inferior study,
there was a predefined letter score of plus or
minus five letters. So if the Lucentis-treated group
ended up within plus or minus five letters of the pan-retinal
photocoagulation group, then the study finding will show
that the Lucentis treatment would be non-inferior. If Lucentis group did not come
close to five letters to the pan-retinal photocoagulation
group, then it would be deemed that the anti-VEGF therapy would
not be beneficial for the treatment of proliferative
diabetic retinopathy. So, what did the study find? The study found that
Lucentis-treated group, shown on the dotted line on the slide, at
two years or 104 weeks, there was an improvement of 2.8
letters compared to baseline. How about the laser group? The PRP group improved
only 0.2 letters or nearly the same as the baseline. And the difference between the
two groups, the PRP group and the Lucentis group,
were within five letters. So the endpoint of showing using
anti-VEGF therapy for management of proliferative diabetic
retinopathy is non-inferior to the current therapy for
proliferative diabetic retinopathy, namely pan-retinal
photocoagulation, has been met. Furthermore, the study found
that treatment with the anti-VEGF such as Lucentis had
less damage to the peripheral vision such that Lucentis group
on average lost only 23 decibels on a visual field testing,
whereas the PRP group lost 422 decibels, and this difference
between the two groups were statistically significant. As for safety, injection with
the anti-VEGF agent Lucentis did not show any increase in
complications such as retinal detachment, development of
new blood vessels such that neovascular glaucoma occurring
or neovascularization occurring or bleeding in the eye or
vitreous hemorrhage occurring compared to the PRP group. Interestingly, the Lucentis
group had far less number of vitrectomy surgeries needed
compared to the laser group, 4 percent in the Lucentis group
compared to the PRP group, so there may be additional
benefits of using Lucentis for proliferative diabetic
retinopathy versus pan-retinal photocoagulation. In summary, what did we learn
from Protocol S, which was for proliferative diabetic
retinopathy management? We found that treatment with
intravitreal anti-VEGF agent was not worse than pan-retinal
photocoagulation for vision outcomes at two years. Furthermore, there was superior
mean visual field outcome, meaning the anti-VEGF therapy
did not cause more visual field defects compared to the PRP, and
there was also a decreased need for vitrectomy surgery. So anti-VEGF treatment may
reduce the need for destructive treatment such as pan-retinal
photocoagulation. In summary then, we are
now entering a new era of diabetic retinopathy treatment. In the 70s and 80s, we learned
that laser photocoagulation can be helpful in preventing vision
loss due to diabetic macular edema and proliferative
diabetic retinopathy. Over the last decade, many of
these exciting new clinical trials and innovations have
developed such that now we can improve vision in patients with
diabetic macular edema much more than we were able to do with
focal grid laser treatments by utilizing these
anti-VEGF agents. Now, anti-VEGF agents do
have side effects, such as possible increase in risk of
retinal detachment or intraocular infections,
called endophthalmitis. Also injections may need to be
performed every 4 weeks initially for a
number of visits. So I would say for patients
with proliferative diabetic retinopathy, who will require at
least six injections that are performed monthly with
anti-VEGF agents. If the patients cannot come
in that often, we may still perform pan-retinal
photocoagulation. However, in ideal patients who
are willing to spare their peripheral vision and are
willing to come in monthly for anti-VEGF agent injections
to initially stabilize their proliferative diabetic
retinopathy, anti-VEGF agents may be considered before trying
the pan-retinal photocoagulation for management of proliferative
diabetic retinopathy. So, these are exciting times. We now have more than one
treatment option under our belt for improving vision and
saving vision in our patients with diabetes. We can still perform laser
photocoagulation as needed but, in many cases, especially for
management of diabetic macular edema, first-line therapy will
be utilizing one of these anti-VEGF agents. And for proliferative diabetic
retinopathy based on the patients and their needs, we can
consider either pan-retinal photocoagulation or starting
with anti-VEGF therapy intravitreally followed by
pan-retinal photocoagulation as needed. Thank you for your attention. Neyal Ammary-Risch: Great. Thank you so much, Judy, and
thank you, Emily, for the great overview. It’s very comprehensive, and I
know that there’s a lot to take in, but you know, one of the
things that I think it’s really important to stress is that
newer treatments mean better outcomes, and I’d say we have a
lot of work to do because we know that only half of people
with diabetes get an annual comprehensive dilated eye exam,
which is recommended to detect diabetic eye disease early. So people do not need to go
blind or lose a lot of vision from diabetes, and I think this
is something really important for us to stress that early
detection and treatment are really key to preventing vision
loss, and I wanted to talk a little bit about some of the
educational resources we have available, so everyone working
with people with diabetes can play a role in their eye
health education and preventing vision loss. So what can you do? Educate people about diabetic
retinopathy and the importance of diabetes control and
encourage people with diabetes to get the dilated eye exam
every year and also keep their health on TRACK. TRACK is a message that the
National Eye Health Education Program stresses through a lot
of our diabetic eye disease messaging, talking about the
importance of taking medications as prescribed by a healthcare
provider, reaching and maintaining a healthy weight,
adding physical activity to the daily routine, controlling their
A1cs, blood pressure, and cholesterol—we know that’s
important from what Emily has discussed earlier—and then
kicking the smoking habit. So, our diabetic eye disease
program is really designed to help raise awareness about
diabetic eye disease and the importance of having that
dilated eye exam. A lot of our program materials
stress that diabetic eye disease often has no early warning signs
or symptoms, that early detection, timely treatment, and
appropriate follow-up care can prevent up to 95 percent of
vision loss and, again, people need to have an eye
exam at least once a year. And I think it’s really
important there are no symptoms in the early stages. It’s something we really need to
tell people because a lot of times people are often waiting
until they’re getting symptoms to see an eye care provider, and
that’s often the time when treatment is—couldn’t be as
effective as it was if people are diagnosed earlier. So where can you find a
lot of our materials? Our website is here,
www.nei.nih.gov/nehep, for those of you who are just
listening in right now. We have a lot of educational
resources to the patients and with those in your community. So if you’re doing diabetes
self-management programs, if you’re working in communities,
or if you have educational resources in your clinic,
it’s a nice opportunity to share information. This slide just shows kind of a
collection of what the National Eye Institute and the
NEHEP program offer. We have booklets that you can
download and give to patients of what you should know about
diabetic retinopathy, for a patient who’s newly diagnosed,
and it kind of talks about what diabetic retinopathy is and the
treatments available that Judy and Emily had
just spoken about. We have a lot of infographics
and infocards for those of you who are doing social media. For your clinics and practices
have your own Facebook and Twitter feeds, it’s a nice
opportunity to share some of that information. As far as the tip sheets, we
offer tip sheets to health and community professionals to try
and tailor information to some of the populations that you’re
working with, so you, if you work with a large
African-American population or a Hispanic and Latino population,
how to tailor some of your efforts in terms of outreach,
make them a little more culturally and linguistically
appropriate and making sure that you know what resources are
available from the NEHEP program to help you. And we also have
animations and videos. Some really nice ones around
diabetic retinopathy, one that talks about how diabetic
retinopathy impacts the eye. We have a really unique video
that shows what a dilated eye exam looks like from a doctor’s
point of view and that’s a really nice patient education
tool that you can show to your patients to show them this is
what I’m looking for when I do a dilated eye exam and this is
what the retina may look like. So, we really encourage you to
use those resources as well as other teaching tools that
you can download directly from our website. One new tip sheet that I want
to point out that we’ve just released a couple of months
ago is our Treating Diabetic Retinopathy fact sheet, and it’s
a really patient-friendly resource that you can
print and give to folks. It gives a brief overview of
what diabetic retinopathy is, how patients can protect their
vision, and then talks about the various treatments that are
available related to the various drugs that Judy has just given
an overview of, and then it gives them some websites and the
places that they can go to get additional information. And I mentioned
social media resources. And these are just a few that we
offer on diabetic retinopathy just to encourage
people to get an eye exam. So these are again all
downloadable from our website, in the public domain since we’re
a federal government agency, so you can take and
use these and you can add your logos to them, as well. Our contact information is here,
and I also invite you to join us on our social media networks
where we’re putting out a lot of educational information that
you’re welcome to share with the folks in your community and
the patients that you see. So some of the questions that we
have—Judy, there’s a question about, “Is there a group of
patients that benefit the most from anti-VEGF therapies?” Judy Kim: So
currently, the group that benefits the most are those
with diabetic macular edema that shows swelling right at the
center of the retina and are quite thickened, based on OCT. And when they’re given anti-VEGF
agents, it’s pretty remarkable how well many of them can
decrease the thickness and improve vision in many cases. Neyal Ammary-Risch:
Great. Thank you. So Emily, this is a
question for you. Any ideas on why the increased
deaths in the intensive glycemic control group for the study that
you spoke of earlier, were they hypoglycemia related? What benefits are seen with
lipid controls? What benefits are seen in the
blood pressure control and what about intensive control of all
three parameters? Emily Chew: Well, this question
really points to the ACCORD study, the Action to Control
Cardiovascular Risk in Diabetes. We had a actually premature
closing of the glycemic arm of the study because there
were more deaths in the patients who were put intensive groups. It was not a huge number, it was
a 20 percent increase but the number itself were small,
but we never could understand why that was. We looked at hypoglycemia, that
was not the reason with the different drugs, looking at
their comorbidity such as their heart disease, we really did
not find a reason as to why there were more. In terms of the cardiovascular,
this study was designed to look at heart outcomes, looking at
heart attacks, strokes, and other things, and we found that
the blood pressure control was important in reducing stroke but
overall, the heart disease is not reduced at all by
any of the three arms. And the eyes, which was the main
thing that in which there was some effect from the glycemia as
well as the Fenofibrate. Judy Kim: Now, can I also go
back to my first question about which group benefits the most? I want to stress the point that
you were pointing out that the eyes that were found to have
macular edema, recently they are the ones that benefit, and,
therefore, it’s very important that we identify eyes with
disease earlier rather than later because if the macular
edema has been quite chronic of long duration, they may
not respond as well. The OCT may improve, but the
vision may not improve. Also, even if the vision is poor
at baseline, if the disease was found early enough, then they
will also improve vision, but if the vision is poor and it’s been
chronic disease, then they don’t respond as well either. So, again, I want to stress the
early detection of diabetic macular edema and retinopathy
with the annual eye check-up. Neyal Ammary-Risch:
Great. Thanks. This question I’ll give to
Emily, “What is the rule for nutritional intervention if
relevant to people with diabetes to control
diabetic retinopathy?” Emily Chew: We don’t have any
clear data suggesting that it’s important, but obviously you
have to eat well and have a balanced diet, and keeping your
weight in a normal fashion both with diet and physical
exercise is very important. The Diabetes Prevention Program
shows that just losing weight can be very important in
reducing the risk of developing diabetes. So although we don’t have
anything to suggest that having certain vitamins or certain food
will be important, we do know that it is important to have a
good balanced diet. And we know from the heart point
of view that eating fish twice a week is good for your heart. So people who have diabetes have
a three- to four-time increase with the cardiovascular disease,
so it’s very important to have a good heart-healthy
diet as well, too. Neyal Ammary-Risch:
Great. Thank you. And since we’re out of time,
again I would like to thank Drs. Chew and Kim
for their time. Thank you and please
feel free to contact us with any questions.

2 Replies to “Webinar: Advances in the treatment of diabetic retinopathy”

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