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Current Management of
Diabetic Macular Edema
and Diabetic Retinopathy
Original Release: January 2, 2015
Last Review: December 9, 2014
Expiration: January 31, 2016
This continuing medical education activity is jointly provided by the University of Nebraska Medical Center, Center for Continuing Education and MedEdicus LLC.
This continuing medical education activity is supported through an unrestricted educational grant from Regeneron Pharmaceuticals, Inc. This activity intends to educate retina This continuing medical education activity is specialists, retina fellows, and comprehensive supported through an unrestricted educational ophthalmologists caring for patients with DR/DME.
grant from Regeneron Pharmaceuticals, Inc. Learning Objectives
Upon completion of this activity, participants will Diana V. Do, MD, had a financial relationship
be better able to: during the past year with the following • Recognize the importance of individualized commercial interests that produce health care- glycemic control in optimizing outcomes for related products and/or services in the form of patients with DR/DME Consultant: Allergan, Inc; Genentech, Inc; and Quan D. Nguyen, MD, MSc
• Discuss the utility of different diagnostic Regeneron Pharmaceuticals, Inc.
imaging techniques in guiding the Professor and Chair Jeffrey S. Heier, MD, had a financial relationship
management of patients with DR/DME during the past year with the following • Describe the efficacy, dosing, and safety profiles McGaw Memorial Endowed Chair commercial interests that produce health care- of current and emerging treatment options related products and/or services in the form of Grants/Research Support Recipient: Aerpio Director of the Stanley M. Truhlsen • Confidently tailor diagnostic and treatment Therapeutics; Genentech, Inc; and Regeneron strategies for various patients with DR/DME Pharmaceuticals, Inc; Consultant: Aerpio University of Nebraska • Communicate effectively with referring Therapeutics; Allegro Ophthalmics, LLC; physicians regarding the relevant systemic and Genentech, Inc; Kala Pharmaceuticals Inc; ophthalmic health issues of their mutual Regeneron Pharmaceuticals, Inc; and Stealth patients with DR/DME Diana V. Do, MD
Joint Providership Credit Statement
Quan D. Nguyen, MD, MSc, had a financial
This activity has been planned and implemented relationship during the past year with the Associate Professor of Ophthalmology in accordance with the accreditation following commercial interests that produce Vice Chair for Education requirements and policies of the Accreditation health care-related products and/or services in Director of the Carl Camras Center Council for Continuing Medical Education the form of Grants/Research Support Recipient for Innovative Clinical Trials through the joint providership of the University of and Scientific Advisory Board: Bausch + Lomb Nebraska Medical Center, Center for Continuing Incorporated; Genentech, Inc; Regeneron Director of the Ophthalmology Education and MedEdicus LLC.
Pharmaceuticals, Inc; and Santen Residency Training Program Pharmaceutical Co, Ltd. University of Nebraska The University of Nebraska Medical Center, Anne Peters, MD, had a financial relationship
Center for Continuing Education is accredited by during the past year with the following the Accreditation Council for Continuing Medical commercial interests that produce health care- Education to provide continuing medical related products and/or services in the form of Jeffrey S. Heier, MD
education for physicians. Grants/Research Support Recipient: Medtronic Director, Vitreoretinal Service MiniMed, Inc; Consultant: Abbott Diabetes Care The University of Nebraska Medical Center, Ophthalmic Consultants of Boston Inc; Becton, Dickinson and Company; Bristol- Center for Continuing Education designates this Boston, Massachusetts Myers Squibb/AstraZeneca; Eli Lilly and enduring material for a maximum of 1.5 AMA Company; Janssen Pharmaceuticals, Inc; PRA Category 1 Credits™. Physicians should Anne Peters, MD
Medtronic MiniMed, Inc; Novo Nordisk; and claim only the credit commensurate with the Professor of Medicine Sanofi; Speakers Bureau: Bristol-Myers extent of their participation in the activity.
Director, University of Southern Squibb/AstraZeneca; and Novo Nordisk.
California Westside Center To Obtain AMA PRA Category 1 Credit™
It is the policy of the University of Nebraska To obtain AMA PRA Category 1 Credit™ for this Medical Center to ensure balance, Keck Medicine of University activity, read the material in its entirety and independence, objectivity, and scientific rigor in of Southern California consult referenced sources as necessary.
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Regeneron Pharmaceuticals, Inc; or Retina.
then remained.13 The patients who were tightly controlled during the trial found it too difficult to maintain their HbA1c levels at 7%, even with the tools and resources Optimal management strategies for patients with diabetic made available to them. Without the active conditions of retinopathy (DR) and diabetic macular edema (DME) the trial, the median HbA1c levels of the intensively treated continue to evolve at a rapid pace. Careful consideration patients went from 7.2% to 7.9%.13 of numerous patient factors and treatment options is essential to the generation of positive visual outcomes. To From these results, the phenomenon of metabolic memory that end, we convened a multidisciplinary panel to discuss was noted. If a patient's HbA1c is 9% for 10 years and is current approaches to successful management of patients subsequently lowered to 7% for the next 10 years, the risk for with DR or DME. We have selected several challenging microvascular and macrovascular complications is much case scenarios that will highlight management options worse than if the HbA1c starts out at 7% for the first 10 years such as laser photocoagulation, anti-vascular endothelial and then increases to 9% for the second 10 years. There is growth factor (VEGF) therapies, intravitreal steroids, and something about that first phase of diabetes during which if glycemic control. tight control is achieved, long-term outcomes are improved.
—Quan Dong Nguyen, MD, MSc This is what was observed in the sustained follow-up to the DCCT and the Epidemiology of Diabetes Interventions and Complications (EDIC)—the intensive therapy group Glycemic Control Strategies
continues to do better for many years. In a recent study, the risk for further progression of retinopathy, progression to Dr Peters: The recently published position statement of the
proliferative diabetic retinopathy (PDR), clinically significant American Diabetes Association (ADA) for the treatment of macular edema, and the need for intervention type 1 diabetes mellitus addresses this condition across the (photocoagulation or anti-VEGF) over 18 years of follow-up in life span,1 and although we think of type 1 diabetes as a the DCCT/EDIC were described.14 Although the cumulative predominantly pediatric disease, it can develop at any age.
incidence of these outcomes continues to be lower in the In the United States, there are as many as 3 million patients group that initially received intensive treatment, the annual with type 1 diabetes,2 with approximately 167,000 of them incidence of these outcomes is now comparable between being children or youths.3 Historically, HbA1c targets for groups, largely because of a reduction in risk in the group children were higher than those for adults because of the that initially received conventional treatment.14 premise that severe, recurrent hypoglycemia in children was associated with neurocognitive compromise,4 and that There are other instances of metabolic memory found in childhood was protective with respect to hyperglycemia.5,6 large studies looking at patients with type 2 diabetes.15,16 The concerns pertaining to hypoglycemia and The UK Prospective Diabetes Study (UKPDS) also showed neurocognitive problems have been allayed,1,7,8 and early the benefit of early tight glycemic control. These patients hyperglycemia and glucose variability may pose risk to the had been recently diagnosed with type 2 diabetes and central nervous system.9 randomized to 1 of 2 arms: an intensive treatment arm (with either a sulfonylurea or insulin) or a conventional On the other hand, people with type 1 diabetes used to diet-controlled arm.15 The intensively treated patients had die before they reached advanced age because of a 12% reduction in all diabetes-related end points over hypoglycemia and other complications. Now, patients with 10 years (P=.029) and a 25% reduction in the risk for type 1 diabetes are living longer.10,11 We have lowered microvascular end points, largely because of the reduced pediatric targets and raised targets for older adults.1 Our need for laser photocoagulation.15 As in DCCT, the patients' knowledge about type 1 diabetes is ever increasing, and HbA1c values tended to drift up over time in the follow-up we are doing more type 1-focused research.
study, but the benefits of early tight control were demonstrated with a persistent 24% relative reduction in Clinical evidence has supported the benefits of glycemic risk for microvascular disease (P=.001).17 Later tight control control for patients with type 1 diabetes, with studies such may not be as beneficial. as the Diabetes Control and Complications Trial (DCCT), which showed unequivocally that for the pathognomonic How well are we doing? The Helmsley Charitable Trust has complication for type 1 diabetes, DR,12 there is tremendous established a registry of more than 26,000 patients from benefit associated with intensive therapy. In the primary- approximately 60 type 1 diabetes clinical centers in the prevention cohort of the DCCT, there was a 76% reduction United States, and it has shown that even the best centers in the adjusted mean risk for retinopathy development for are not able to get the average HbA1c of their patients to those patients who received intensive therapy.12 With less than 7%.18 Adolescence is a particularly difficult time respect to the secondary-intervention cohort, the for glycemic control,3,19 whereas older patients tend to do progression of retinopathy was slowed by 54%, and the better. Approximately 27% to 34% of adults are at target.20 development of proliferative or severe nonproliferative The frequency of severe hypoglycemia increases with age, retinopathy was reduced by 47%.12 Benefits were greater and this is why the HbA1c targets for older patients with in those patients who started intensive therapy earlier. type 1 diabetes are not more aggressive.1 If a patient is aged 65 years or older and has comorbidities and/or a It is extremely difficult to achieve the same level of short life expectancy, the HbA1c target becomes greater glycemic control in patients with type 1 diabetes in the than 7.5%.1 If the patient is particularly complex or in poor world outside of clinical trials, because patients are trying health, it becomes extremely difficult to establish a target to balance high and low blood sugars often without without increasing risk to the patient.1,21 the assistance of expert diabetes clinicians. When the individuals in the control arm of the DCCT were made When considering a strategy for glycemic control for aware of the data from the trial, they lowered their HbA1c patients with type 2 diabetes, the ADA/European levels from a median value of 9.1% to 8.2%, where they Association for the Study of Diabetes (EASD) position statement advocates a patient-centered approach. The receptor agonist, sodium-glucose co-transporter 2 other members of the Writing Group and I thoroughly inhibitors, and metformin. Treatment of type 2 diabetes reviewed the available evidence when we put the has become much easier to manage given the new (along statement together, and our recommendations are less with some of the old) medications we have available. algorithmic than previous approaches. Comparative efficacy studies are limited; with respect to pharmacotherapy, metformin should generally be regarded as the optimal first-line drug, unless it is Dr Do: A 38-year-old gentleman with a history of type 1
contraindicated.22 After that, the picture is less clear. The diabetes came in for his annual eye examination a few Group spent hours looking at this and we were not able to months ago. At the time of presentation, he had been establish a definitive second-line step because of several bothered by occasional blurred vision for several months.
variables such as practice setting, individual patient His HbA1c was 7.0% three months prior to presentation. characteristics, financial considerations, and the role of His visual acuity was 20/30 in the right eye and 20/20 in the left eye. A dilated examination showed some hard exudates and some mild macular edema (Figure 1).
Looking at the clinical trials, in addition to UKPDS and DCCT, Dr Nguyen, when you assess your patients for suspected there also are data from ACCORD,23,24 ADVANCE,25 and DME, what imaging test(s) do you routinely obtain? VADT.26 These trials were conducted in older patients who had complications, many of whom had had macrovascular events. It was thought that tightening glycemic control would result in improved macrovascular outcomes. In the latter 3 studies, some microvascular end points (pertaining to retinopathy, nephropathy, and neuropathy) showed a degree of improvement with tight control. In ACCORD, the HbA1c target was below 6%.23 Trying toreach this target actually increased mortality, and the Figure 1: Case 1 dilated
study was stopped after a mean of 3.5 years of follow-up.23 Were these deaths due to the development of Photo Courtesy of hypoglycemia among patients? This turned out not to be Diana V. Do, MD the case.27,28 If a person with diabetes develops severe hypoglycemia, whether on intensive therapy or not, it has been shown that the risk for death increases 2- to 4-fold.27 For patients with long-standing diabetes, pushing Dr Nguyen: In patients with new onset DME, I will obtain
their HbA1c values down with drugs that can cause fluorescein angiography,29 as well as spectral domain hypoglycemia is potentially dangerous. However, in optical coherence tomography (OCT).30 If possible, the addition to the finding of the risk for severe hypoglycemia fluorescein angiogram could be done in a wide-angle (noted in all studies), in ACCORD the treatment approach system in order to assess the vasculature in the peripheral designed to lower the HbA1c to less than 6% seemed to increase mortality. It is doubtful an explanation for this will be forthcoming, because all analyses done to date have Dr Do: Dr Heier, what are your thoughts on the necessity of
been negative, but this study has changed current angiography, given the sensitivity of OCT and the fact that practice approaches and made individualization of A1C many of our randomized clinical trials have not really targets mandatory.
mandated the use of angiography? In the aforementioned ADA/EASD position statement on Dr Heier: I absolutely think that angiography is necessary.
type 2 diabetes, we focused on several domains when In a straightforward patient like this, the OCT might show trying to individualize a patient's target HbA1c.22 These edema, and it might be fine for managing this particular domains are all-encompassing, addressing the risk for patient. There are patients, however, who may have what complications, patient life expectancy, disease duration, appears to be relatively subtle disease, and if they have cardiovascular disease, and other factors. The goal is to had diabetes for years, you can see gross nonperfusion balance the patient with respect to all these domains, and and unexpected neovascularization.32 I always obtain a to arrive at an individualized target.
baseline fluorescein angiogram in patients with diabetes and unexplained loss of visual acuity; I may not get In the real world, patients exhibit a huge amount of another one for years if the patient's disease is easily variability with respect to these individual domains. Some managed after initial assessment. patients may be very worried about retinopathy, but severe underlying cardiovascular disease may limit how Dr Do: With this particular patient, we obtained both a
aggressive clinicians can be with glycemic control. Each fluorescein angiogram and an OCT (Figure 2). On the
patient should have his or her own target. The goal is to get angiogram, there is evidence of leakage in the parafoveal as close to normal blood sugar levels as possible without region, and the OCT shows center-involved DME. causing hypoglycemia or other adverse side effects. He had not had any previous treatment. Dr Heier, for this In order to minimize the risks of pharmacotherapy, my patient who has a visual acuity of 20/30 and complains of preference is to use drugs that do not cause hypoglycemia occasional blurriness, what treatment option would you and weight gain, and we have a lot of options to that end.
If patients are willing to work with me, I can usually get even those with advanced type 2 diabetes to target using Dr Heier: I am a little hesitant to start this patient on anti-
a combination of basal insulin, a glucagon-like peptide-1 VEGF therapy at this early stage. His HbA1c of 7.0% is fair,
Glycemic Control Questions on the Minds
of Practicing Retina Specialists
Dr Heier: Dr Peters, is there a general target for
early glycemic control? If a patient presents to an ophthalmologist with an HbA1c of 9%, but no Figure 2: Case 1 fluorescein
retinopathy, how aggressive should we be in initiating angiogram and OCT. a referral to an endocrinologist? Photos Courtesy of Dr Peters: Certainly an HbA
Diana V. Do, MD 1c of 9% is always concerning, and that patient should be seen by an endocrinologist. That being said, it is still important to establish what the individual patient's target is. It is also important for the patient and for all the medical providers involved with the patient's care to establish which provider is setting the patient's target. Dr Nguyen: Do you believe that all patients with
diabetes should be managed by an endocrinologist? Dr Peters: I think that all patients with type 1 diabetes,
if possible, should be monitored by an endocrinologist because of the technical complexity of ongoing but I would want to know if it was lower in the previous management. I think that the vast majority of patients assessments. I have had patients who averaged 6.0%, with type 2 diabetes have to be managed in a primary lost that level of control for a little bit, and subsequently care setting. There are relatively few endocrinologists developed fluid. Unless patients are very symptomatic, I who focus primarily on the management of diabetes. might try a short period of attempting to restore glycemic If a patient with type 2 diabetes is complicated or control (3-6 months often allows an adequate period for having difficulty getting into a target range, then that improvement) and managing other factors such as poorly patient should be seen by an endocrinologist. Other controlled hypertension, rather than essentially committing providers, including Certified Diabetes Educators and them to a series of injections. If they are very symptomatic, dietitians, also have an important role. If you can if their control has been excellent, and if their blood connect your patients with the diabetes community, pressure is under good control, I will discuss anti-VEGF that can be very empowering for the patient. therapy with them; and then if I am going to treat, anti- Dr Nguyen: Do you have a morning glucose target in
VEGF would be my treatment of choice. mind for most patients? Dr Do: Dr Nguyen, if you were going to choose an anti-
Dr Peters: The ADA target is between 70 and 130, but if I
VEGF agent, which one would you choose for this patient? have a patient who has difficulties with hypoglycemia, I Let us assume patient insurance coverage and finances would increase the fasting target to 100 to 130. I generally are not factors. aim for between 90 and 130 before meals, but it might be Dr Nguyen: In a case such as this, if finances are not
lower or higher, depending on the individual patient.
a factor, I would choose either ranibizumab or Dr Nguyen: How does the rate of glycemic reduction
aflibercept because both have been US Food and Drug potentially worsen retinopathy? Administration (FDA) approved for the indication of DME. I am comfortable using either drug, but I may prefer Dr Peters: In the DCCT, 13.1% of patients randomized to
ranibizumab because it has a longer record of safety the intensive control arm had worsening of retinopathy since it was approved several years before aflibercept.33,34 within the first year of treatment, compared with 7.6% of the patients assigned to conventional treatment.1 Some Dr Heier: I think most ophthalmologists would choose
of the risk factors for early worsening that were identified bevacizumab as first-line therapy because cost cannot be included higher HbA1c levels at screening and ignored. I have gone on record a number of times stating reduction of these levels within the first 6 months of that I always use bevacizumab as my first-line therapy. treatment. The DCCT authors did not find any evidence I think that patients do well with it, and almost 90% of my supporting the concept that more gradual glycemic patients get bevacizumab. That being said, if cost was not control might be associated with a lower risk for early an issue, I would never use it because of the availability worsening. That being said, they did recommend of FDA-approved drugs that may be more efficacious in ophthalmologic monitoring before initiation of intensive some patients.35 Some information has recently been treatment and at 3-month intervals for the first 6 to 12 released regarding the Diabetic Retinopathy Clinical months of treatment.1 They also recommended delaying Research Network (DRCR.net) Protocol T study, which the initiation of intensive glycemic treatment until the compared the safety and efficacy of 2.0-mg aflibercept, retinopathy was treated, particularly for patients with 1.25-mg bevacizumab, and 0.5-mg ranibizumab in the poorly controlled diabetes.1 The outcomes for those treatment of patients with DME. These data have not patients who were intensively controlled who had early been peer reviewed. They indicate that there may be worsening of retinopathy were the same or better than differences among aflibercept, bevacizumab, and for those in the conventional group who did not have ranibizumab with respect to gains in visual acuity and early worsening.
rates of cardiovascular events.36 1. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116(7):874-886.
Dr Do: Many ophthalmologists are aware of the clinical
trial data showing that center-involved DME is best treated 20 RIDE RISE Pooled
with an intravitreal anti-VEGF agent. One of our first landmark studies was from DRCR.net, which looked at ranibizumab, given with either prompt or deferred laser, and it showed that either dosing regimen of ranibizumab was superior to preservative-free triamcinolone with laser and also superior to focal/grid laser.37 A change, ETDRS letters
Regarding bevacizumab, which is the most popular choice among the American Society of Retina Specialists membership, the BOLT clinical trial that was conducted 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
in the United Kingdom additionally provides us some prospective clinical trial data to suggest that bevacizumab Ranibizumab 0.3 mg
Ranibizumab 0.5 mg
is also an effective option for center-involved DME.38 ETDRS=Early Treatment Diabetic Retinopathy Study.
Aflibercept was recently approved by the FDA for the Figure 4: Mean change in best corrected visual acuity over time,
treatment of DME, based on the 1-year data from the RISE and RIDE 3-year pooled data.33 phase 3 VISTA and VIVID studies.39 Aflibercept treatment, whether dosed every 8 weeks or every 4 weeks, was Returning to our case, the patient's visual acuity remained superior to focal/grid laser, and eyes gained an average of stable after a 1-month period of observation, but his edema 10.5 to 12.5 letters of visual acuity (Figure 3).39 Both dosing
increased on OCT, so I elected to treat him with the only regimens of aflibercept had similar efficacy. We also have on-label anti-VEGF treatment available at the time, some of the 2-year data from VISTA, and both dosing ranibizumab. I gave him 1 dose, but his visual acuity did regimens resulted in sustained visual acuity with similar not improve significantly, and his edema persisted. Anti-Platelet Trialists' Collaboration-defined arterial I administered a second ranibizumab injection, and his thromboembolic events across all groups.40 visual acuity improved to 20/25 with some decrease in central retinal thickness. After a third ranibizumab injection, his visual acuity improved to 20/20 and the center-involved Another FDA-approved treatment option that exists for patients with DME is the A (letters) 15
dexamethasone delivery device.* The MEAD study looked at the safety and efficacy of this option, and in a recent subanalysis of the study, dexamethasone was found to be more effective than sham therapy in all subgroups, regardless of duration of DME, type of DME, duration of Mean change from Baseline BCV
diabetes, patient age, or perfusion status.41 12 16 20 24 28 32 36 40 44 48 52
12 16 20 24 28 32 36 40 44 48 52
Patients who were pseudophakic at Time (weeks)
baseline showed benefit from dexamethasone at each chronological BCVA=best corrected visual acuity; IAI=intravitreal aflibercept injection.
point that was evaluated, while patients who were phakic at baseline did not show Figure 3: Mean standard deviation change in best corrected
continued benefit from dexamethasone visual acuity from baseline through week 52 with censoring of after the first year of treatment because of the emergence values after additional treatment was given (last observation of cataracts. However, when these patients had their carried forward).39 cataracts removed, their visual acuity results were comparable to those patients who were pseudophakic at baseline. We do not know the optimal dosing strategy When we further probe our armamentarium, we see that for this implant; in recent phase 3 clinical trials, the RISE and RIDE studies demonstrated the superiority of dexamethasone was given every 6 months.42 Most ranibizumab to sham treatment.33 Looking at the extension of us would say that it needs to be dosed every 3 to 4 study, patients who were initially randomized to sham months, according to our clinical experience with the treatment and crossed over to treatment with ranibizumab dexamethasone implant for retinal vein occlusion. 2 years later never matched the gains in visual acuity Dr Nguyen, when would you recommend the seen in patients who were initially treated with dexamethasone implant for DME? ranibizumab (Figure 4).33
Dr Nguyen: I would tend to select anti-VEGF therapy as an
This suggests that a long delay in beginning anti-VEGF initial treatment based on the clinical outcomes data. If therapy for DME causes some level of irreversible damage you compare the overall gains in vision and percentage to the retina, and those eyes will not catch up to eyes that of patients who gained more than 3 lines of vision in began anti-VEGF therapy much earlier. Maybe you could RISE/RIDE and VISTA/VIVID against the gains in the recent delay for a few months, but certainly do not delay for a dexamethasone study, the anti-VEGF therapies had an period of years. * A fluocinolone delivery device also has been approved by the FDA recently for the treatment of DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. It is expected to be available early 2015.
Dr Do: Dr Heier, if we are concerned about the treatment
Metabolic Parameters and the Response
burden to the patient and the patient's family, then the to Pharmacotherapy in DME
dexamethasone delivery device may be an attractive treatment option because it can be given every 3 to 4 Given the prominent role of anti-VEGF therapy and months. For some patients, this interval might even be steroid therapy in the armamentarium for the treatment stretched out further. What is your perspective on the of DME, it is important to assess parameters that may influence their efficacy. Although no double-masked prospective studies have been conducted to assess Dr Heier: I am happy that the dexamethasone implant
the relationship between glycemic control and was approved, and I do think that it will help some of our responsiveness to pharmacotherapy for patients with patients. But I still think that anti-VEGF therapy is the best DME, the question has been addressed with other first line of therapy, largely for its safety profile. Although investigations. The limitations of investigation designs cataracts would not be an issue for the pseudophakic and variation in results have hindered the ability to patient, the problem of treatment-induced glaucoma draw any definitive conclusions. remains,42 and patients with diabetes are already more likely to have elevations in intraocular pressure than A recent subanalysis of the MEAD data, which looked at the role of intravitreal dexamethasone implant therapy patients without diabetes.43 As you mentioned, I believe in the treatment of DME, found that there was a trend that the number of patients who will be able to get to toward greater influence of dexamethasone in patients 6 months with 1 implant will be relatively low. Three to who had better control of their diabetes.1 4 months seems a more likely interval.
A retrospective study conducted by Ozturk and Dr Nguyen: Dr Peters, if a patient's HbA1c is between 7%
colleagues was designed to assess the effects of glucose and 7.5%, and he or she continues to have problems with regulation on visual outcomes for patients with DME recurrent macular edema, is there any utility to lowering who were treated with ranibizumab. In this study, the the patient's HbA1c further? patients' HbA1c values negatively correlated with Dr Peters: I think that there is a benefit regarding the
the change in central subfield macular thickness retinopathy issue. I am not sure there is always a benefit in (coefficient = –0.50, P<.001).2 terms of the entire person, and that is where we providers Another recent retrospective case analysis conducted have to collaborate. Some patients are quite fragile, and by Matsuda and colleagues enrolled 124 consecutive the risks for hypoglycemia are too great. patients with DME to determine the role of systemic factors on functional and anatomic outcomes of anti- VEGF therapy (bevacizumab).3 Patients with a serum Dr Heier: This case features a 36-year-old woman with a 25-
HbA1c of ≤7.0% had a more robust response with respect to best corrected visual acuity and central subfield year history of type 1 diabetes who presented with a 5-day macular thickness than those whose HbA history of "black blobs" in the central vision of her right eye.
>7.0%. Patients whose glycemic control improved during Her most recent HbA1c was 8%. She received panretinal the study had lower retinal thickness than patients photocoagulation in her right eye and focal treatment in her left eye in 2011 (the laser was performed prior to our 1c was stable or had deteriorated.3 care of her). Her visual acuity at the time of presentation 1. Loewenstein A. MEAD: Diabetic Macular Edema Trial Subanalysis. Presented was 20/25 in her right eye and 20/20 in the left. at: Retina Subspecialty Day, American Academy of Ophthalmology. October 17-18, 2014; Chicago, IL. The patient's imaging shows some preretinal hemorrhage 2. Ozturk BT, Kerimoglu H, Adam M, Gunduz K, Okudan S. Glucose regulation influences treatment outcome in ranibizumab treatment for diabetic macular inferiorly in the right eye; there is evidence of previous edema. J Diabetes Complications. 2011;25(5):298-302.
laser. The left eye looks good. Dr Do, how would you 3. Matsuda S, Tam T, Singh RP, et al. The impact of metabolic parameters on suggest this patient be managed? clinical response to VEGF inhibitors for diabetic macular edema. J Diabetes Dr Do: I would recommend obtaining a fluorescein
angiogram to evaluate the retinal vasculature.29 I suspect that there will be significant capillary nonperfusion and multiple areas of neovascularization in her right eye. She may have more retinopathy problems with her left eye as well. If this patient has poor glycemic control, retinopathy is likely to be fairly symmetric in both eyes. Dr Heier: You are correct. There are some areas of
neovascularization and perhaps some capillary nonperfusion. Her widefield angiogram shows that there are a number of areas of neovascularization and extensive capillary nonperfusion (Figure 5). Dr Nguyen, how would
you approach this patient? Dr Nguyen: This patient has PDR that seems to be laser
deficient at the time of this imaging. I would perform additional panretinal photocoagulation, because there is evidence to support its efficacy in controlling the progression of the PDR.29,44 Because there is no macular Figure 5: Case 2 widefield angiogram (OD).
edema, I would delay pharmacologic therapy at this time. Photo Courtesy of Jeffrey S. Heier, MD
Dr Heier: Dr Do, if there was macular edema, would you
a much greater extent of disease pathology than does approach this patient differently? 7 standard field imaging, and may, in fact, alter the classification of DR in as many as 10% of eyes evaluated Dr Do: I would recommend anti-VEGF injection to treat the
by the 7 standard field imaging technique.32,48 macular edema, and panretinal photocoagulation laser to control the proliferative aspect. I get baseline widefield imaging on every patient with diabetes, as well as on patients with retinal vein occlusion.
Dr Heier: Would you administer these 2 treatment
For this particular patient, we were amazed by the extent modalities at the same time or would you do the anti-VEGF of disease in her left eye. first and then the laser? Dr Do, when treating a patient with DR with anti-VEGF Dr Do: I tend to do both procedures at the same visit to
therapy, do you follow the patient with angiography? avoid the need for the patient to come back multiple times. I also try to do all the panretinal photocoagulation Dr Do: I think that when treating DME, an angiogram at
baseline is helpful. For routine follow-up and ongoing management decisions, OCT is more practical. In my Dr Peters: This young woman is the perfect example of a
opinion, you need to repeat the angiogram only if patient who should be referred to an endocrinologist, if she something changes or if the patient does not respond as is not already under the care of one. Given the fact that you would expect. she is of reproductive age, any attempts to treat her ophthalmic problems would be significantly complicated Dr Heier: We have recently conducted a study looking at
by a pregnancy.45 Contraception should be discussed. You just such an issue, and we are currently evaluating the do not want a patient with poor glycemic control or results.49 We treated patients who had PDR with either 12 unstable vision becoming pregnant. monthly injections of aflibercept or 6 monthly injections followed by a period of 6 months during which the Dr Do: Yes, I agree completely. We do not know the effects
injections were given every other month. We then followed of anti-VEGF therapy on pregnant women, so we certainly the patients with widefield angiography, with the intent of do not advocate using it in patients who are pregnant. We examining the degree of nonperfusion and how the anti- always counsel our young female patients to use a reliable VEGF therapy affected it.49 I expect to have those results birth control method, as you have advised. If this patient with progressive eye disease was to become pregnant, I would attempt focal/grid laser first for DME, because that is the safest option.46 If the edema does not Dr Do: We next have a case of a 62-year-old woman with
respond, and her vision is being further compromised, a 5-year history of type 2 diabetes who presented with a then an intravitreal steroid injection may be the next complaint of decreased vision in her left eye. Her diabetes best option. The safety of intravitreal anti-VEGF agents was initially treated with oral antiglycemic agents, but she in pregnancy is unclear, and we do not recommend subsequently required insulin. Her most recent HbA1c was anti-VEGF injections in this population.47 In my opinion, 8.5%. At the time of presentation, she was noted to have anti-VEGF would be a first-line agent for women of center-involved DME in her left eye with a visual acuity of reproductive age who have diabetes and DME, if they are 20/80 (Figure 7).
able to be reliable with contraception. If not, then laser or intravitreal steroids might be other options to consider. Dr Heier: Let us move on to the patient's left eye; her OCT
shows a few cysts but a nice contour. There is some evidence of neovascularization on her 7 standard field imaging, and on her widefield imaging (Figure 6) gross nonperfusion is evident.
Figure 7: Case 3 baseline OCT OS (20/80–1).
Photo Courtesy of Retina Consultants of Houston Her retina specialist elected to treat her with ranibizumab, and after 1 injection, her visual acuity improved to 20/60.
Her edema was still persistent, and her ophthalmologist administered a second injection. Her vision then was 20/60+2, and her foveal contour returned. Dr Heier, in this patient, would you continue treatment or begin a period of observation at this point? Figure 6: Case 2 widefield angiogram (OS).
Photo Courtesy of Jeffrey S. Heier, MD Dr Heier: I would continue treatment here. As in RISE and
RIDE, we often see slow recovery of vision in patients with Recent studies, such as those conducted at the Joslin diabetes.33 There are still some exudates and fluid Diabetes Center and Weill Cornell Medical Center, have temporarily, so I would continue until I was absolutely shown that ultra-widefield angiography potentially reveals convinced that she had maximized visual gain. Dr Do: Dr Nguyen, do you ever consider combining anti-
Dr Do: That is what her specialist did. He administered
VEGF with laser, and if so, when do you add the laser? another ranibizumab injection. Her macula looked great, with no edema. Her visual acuity improved to 20/40.
Dr Nguyen: I usually start with anti-VEGF injections alone.
If the eye has a suboptimal response to the intravitreal Subsequently, her provider decided to administer yet VEGF blockers, I may switch anti-VEGF agents or add another injection, and her vision improved by 1 line to focal/grid laser to the injections.
20/30. Dr Nguyen, what would you do now? Do you think that the eye will go to 20/20 if you give 1 more injection? Dr Heier: While I am not yet convinced that subthreshold
Should we continue? micropulse diode laser50 will work, if the problem is recurrent, as it is in this scenario, I would be interested Dr Nguyen: She continues to improve, so I would say to
to see if such an approach would help. continue monthly therapy. Dr Do: I know many of our colleagues like to combine
Dr Do: When you look at the visual acuity response curves
the effects of anti-VEGF therapy with focal/grid laser.
from the randomized clinical trials pertaining to the Interestingly, the DRCR.net Protocol I demonstrated that treatment of wet macular degeneration and DME, you can in year 3, eyes randomized to ranibizumab with deferred see that visual gains rise quickly in age-related macular laser (laser given at month 6 or later) had gained almost degeneration (AMD) and may also plateau more quickly 3 letters more compared with eyes randomized to in AMD than they do in DME (Figure 8).33,52
ranibizumab with prompt laser. These data suggested that anti-VEGF treatment with deferred laser may be more We do not know why this slight difference occurs. One beneficial than when laser is used at the beginning.51 study looking at bevacizumab for the treatment of DME found that although anti-VEGF therapy did lower In this case, the patient's retina specialist provided another intraocular VEGF levels dramatically, the effect on other anti-VEGF treatment, and her vision improved to 20/40. cytokines involved in disease progression was not as great Dr Nguyen, what would you do at this time? Would you as it is in AMD.53,54 observe, or continue the anti-VEGF therapy? When would your end point be? Dr Nguyen: The patient has continued to show
Dr Nguyen: I think that there are several key messages to
improvement in vision, so I would like to make sure that highlight. First, we need to be patient with our treatment we have maximized her potential gain in visual acuity. choices with DME, because it appears that the time to I would continue to treat her at this point, because there maximal effect of anti-VEGF therapy may be longer for DME may yet be some level of edema that we could eliminate. than it is for some other retinal vascular diseases. Anti-VEGF therapy does appear to be a therapeutic cornerstone for DME, particularly for those patients with central involvement.
Second, an individualized approach to glycemic control may benefit patients with diabetes more than trying to treat to a specific HbA1c goal. Third, DR and DME are quite complex and variable in their presentations, and it may be worthwhile to consider widefield angiography as a means of detecting and assessing the true scope of these diseases. My appreciation to our panelists for a lively discussion of some essential management strategies for our complex ean Change in Visual Acuity (no. of letters)
patients with DR and DME. An individualized approach can provide great improvements in glycemic control as well as in visual outcomes.
Trial Abbreviations Used
Action to Control Cardiovascular Risk in Diabetes Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema Macular Edema: Assessment of Implantable Dexamethasone in Diabetes ean BCVA Change, ETDRS letters
A study of ranibizumab injection in subjects with clinically significant macular edema with center involvement secondary to diabetes mellitus Ranibizumab 0.3 mg
Ranibizumab 0.5 mg
Veterans Affairs Diabetes Trial Figure 8: Visual acuity response curves from ANCHOR (AMD)52
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CME Post Test Questions
To obtain AMA PRA Category 1 Credit ™, please see detailed instructions on page 2.
1. Which of the following factors would tend to favor more 6. Which of the following statements regarding the stringent management of hyperglycemia for a patient relationship between type 1 diabetes and patient age with type 2 diabetes? a. High level of risk potentially associated with a. Older patients are less successful with glycemic control than adolescent patients b. Low patient motivation b. Approximately 30% of adult patients are at c. Long-standing duration of disease d. Lack of established vascular complications c. The frequency of severe hypoglycemia decreases 2. Which of the following statements regarding the d. Pediatric glycemic goals have been made less management of hyperglycemia in type 1 diabetes stringent because of validated concerns regarding a. Adult glycemic targets are more stringent now than they have ever been 7. A patient with evidence of clinically significant diabetic b. Early problems with hyperglycemia do not macular edema should have an HbA1c target value: predispose children to complications as adults c. Ophthalmologic monitoring should take place before and during the first year of increased glycemic control efforts d. That takes into account multiple individual patient d. Patients with long-standing diabetes should factors, including risk for hypoglycemia always aim for an HbA1c value of ≤6% 8. All the following statements regarding the use of OCT in 3. The use of ultra-widefield angiography for patients with the management of DME are true, except: diabetic macular edema: a. OCT imagery has a high level of correlation with a. Has been mandated as a means of following anatomic outcomes in clinical trials b. OCT is a highly reproducible method of measuring b. Has revealed a correlation between the degree of pathological features of DME retinal ischemia and macular thickness c. OCT can monitor response to therapies such as c. Has the potential to change the classification of a surgical intervention and intravitreal patient's ophthalmic disease d. Has been shown to be less efficacious than d. OCT may be performed in conjunction with 7 standard field imaging as a means of detecting fluorescein angiography diabetic pathology 9. All the following factors may adversely influence visual 4. Dexamethasone implant use for the treatment of health for patients with diabetes, except: diabetic macular edema: a. Is currently FDA approved for pseudophakic adult c. Poor glycemic control b. Provides up to 2 years of medication per implant d. Low serum triglyceride levels c. Carries no appreciable risk for elevations in intraocular pressure 10. When assessing the response of patients with DME to d. Is a Pregnancy Category X treatment anti-VEGF therapy, it is important to consider that: a. Visual gains plateau more quickly in DME than 5. Anti-VEGF therapy for clinically significant diabetic b. Glycemic control influences the efficacy of all a. Is regarded as a first-line choice for this condition when it involves the foveal center c. Prolonged delays in anti-VEGF therapy may limit b. Has worse functional and visual outcomes than the magnitude of visual gains for patients who are laser photocoagulation candidates for it c. Has only 1 FDA-approved option d. Anti-VEGF therapy should be combined with laser d. Typically achieves maximum functional gains therapy within the first month of pharmacologic by 2 months of treatment Activity Evaluation/Credit Request
Original Release: January 2, 2015 • Last Review: December 9, 2014 • Expiration: January 31, 2016
Current Management of Diabetic Macular Edema and Diabetic Retinopathy:
A Multidisciplinary Discussion of Clinical Cases
PARTICIPANT INFORMATION (Please Print)
❏ Home ❏ Office Last Name _ First Name Birth Month/Day (mm/dd) Specialty Degree ❏ MD ❏ DO ❏ OD ❏ PharmD ❏ RPh ❏ NP ❏ RN ❏ PA ❏ Other City State _ ZIP Code Country E-mail Phone Fax _ The objectives were achieved.
Upon completion of this activity, participants will be better able to: Recognize the importance of individualized glycemic control in optimizing outcomes for patients with DR/DME Discuss the utility of different diagnostic imaging techniques in guiding the management of patients with DR/DME Describe the efficacy, dosing, and safety profiles of current and emerging treatment options for DME Confidently tailor diagnostic and treatment strategies for various patients with DR/DME Communicate effectively with referring physicians regarding the relevant systemic and ophthalmic health issues of their mutual patients with DR/DME FINANCIAL INTEREST AND BIAS
Disclosure of relevant financial interests of presenters and planners was stated. ❏ Yes ❏ No This educational activity was free of commercial bias. ❏ Yes ❏ No If no, please explain. IMPLEMENTING INTO PRACTICE
Do you intend to make changes or to apply new knowledge as a result of this educational activity? I intend to make changes to improve my effectiveness. ❏ Yes ❏ No This experience will not change my practice, as my current behavior is already consistent with the information provided. ❏ Yes ❏ No If no, please explain.
What strategies for improvement or changes do you plan to implement following this educational activity? Please indicate all barriers you perceive in implementing these changes. (check all that apply) ❏ Lack of professional guidelines or consensus ❏ Patient compliance issues ❏ Opportunity to practice ❏ Lack of resources ❏ Lack of health system support ❏ Further training is needed ❏ Cost/Reimbursement/Insurance issues ❏ Other, please specify _ How do you think your changes will affect patient outcomes? POST TEST ANSWER BOX
Private experience and observational learning in pharmaceutical demand Tanja Saxell∗† February 13, 2014 I quantify the roles of the physician's own experience and the past choices of other doctorsin pharmaceutical demand. I develop a model of medical decision-making under uncer-tainty about the quality of the match between the patient and drug treatment. Unlikeprevious demand models, I take into account both private and social learning, and allowheterogeneity in product quality across individuals. I test whether information on thepast choices of other doctors improves drug choices. Using rich data from the market forcholesterol drugs, I show that treatment patterns relying heavily on the past choices ofother doctors can lead to over-prescribing in terms of eciency. My results suggest thatcontinuity of care, where a patient is repeatedly consulting the same doctor, is an ecientpolicy to limit such behavior.