Diabetic macular edema (DME) is a common manifestation of diabetic retinopathy (DR) that can have a serious impact on vision, including loss of central vision with related functional impairment. The prevalence of DME increases with the duration of both type 1 and type 2 diabetes. It is estimated that, over 15 years of diagnosed diabetes, approximately 20% of people with type 1 diabetes, 25% of people with type 2 diabetes taking insulin, and 15% of people with type 2 diabetes not taking insulin, will develop DME. The prevalence reaches approximately 30% in those who have had either type of the disease for 20 years.

The incidence of type 2 diabetes has increased in the United States in recent years, in conjunction with an increase in the incidence of obesity.4 This increase, in conjunction with the high incidence of DME in the diabetic population, makes DME a significant public health concern.

TARGET AUDIENCE
This activity is designed for retinal specialists and other ophthalmologists.

LEARNING OBJECTIVES
Upon successful completion of this learning program, the participant should be able to:

• Discuss the prevalence and natural history of DME.

• Cite the results of the DCCT trial and the ETDRS in terms of DME treatments and prevention.

• Explain the rationale, background, and results for laser treatment in DME.

• Discuss the current pharmacological options for the treatment of DME.

• Identify the rationale for the use of steroids in DME treatment and results from published data.

METHOD OF INSTRUCTION
Participants should read the learning objectives and continuing medical education (CME) program in their entirety. After reviewing the material, they must complete the self-assessment test, which consists of a series of multiple-choice questions. This test is available exclusively online, at www.CMEToday.net. Once you register and log in, you can take the test, get real-time results, and print out your certificate. E-mail ckoury@bmctoday.com or call 484-581-1821 if you have any questions or technical problems with the Web site.

Upon completing the activity and achieving a passing score of ≥70% on the self-assessment test, participants can print out a CME credit letter awarding AMA/PRA Category 1 Credit.™ The estimated time to complete this activity is 1 hour.

ACCREDITATION
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Dulaney Foundation and Retina Today.

The Dulaney Foundation designates this educational activity for a maximum of 1 AMA/PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.

DISCLOSURE
In accordance with the disclosure policies of The Dulaney Foundation and to conform with ACCME and FDA guidelines, all program faculty are required to disclose to the activity participants: (1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices, or providers of commercial services that relate to the content of their presentation/material or the commercial contributors of this activity; and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.

FACULTY CREDENTIALS
Michael S. Ip, MD, is from the Department of Ophthalmology and Visual Science, University of Wisconsin, Madison. Dr. Ip is also a member of the Retina Today editorial board. He may be reached at msip@wisc.edu or 608-262-9368.

FACULTY DISCLOSURE DECLARATIONS
Dr. Ip disclosed that he is a consultant for Sirion Therapeutics, Pfizer, Bausch and Lomb, Genentech, and QLT. He is on the speaker’s list for Eli Lilly and Company.

INTRODUCTION
DME, a common manifestation of DR, can have a serious impact on vision, including loss of central vision with related functional impairment. The prevalence of DME increases with the duration of both type 1 and type 2 diabetes.1-3 It is estimated that, during 15 years of diagnosed diabetes, approximately 20% of people with type 1 diabetes, 25% of people with type 2 diabetes on insulin therapy, and 15% of people with type 2 diabetes not on insulin therapy, will develop DME.3 The prevalence reaches approximately 30% in those who have had either type of the disease for 20 years.1

The incidence of type 2 diabetes has increased in the United States in recent years, in conjunction with an increase in the incidence of obesity.4 This increase, in conjunction with the high incidence of DME in the diabetic population, makes DME a significant public health concern.

PROVEN THERAPIES
The only therapies that have been shown in large, long-term, prospective randomized studies to reduce the risk of vision loss from DME are tight control of glucose levels5 and laser photocoagulation6 (Figure 1).

In the Diabetes Control and Complications Trial (DCCT), tight glycemic control resulted in a reduction in risk of onset of DME by almost 25% compared with conventional care over a mean 6.5-year follow-up. In a 4-year extension of that study, risk of development of DME was reduced by 58% with the same regimen of intensive glucose control.7

Focal laser photocoagulation was shown to lower the risk of moderate visual loss in patients with DME by approximately 50% (from 24% to 12%) in the Early Treatment of Diabetic Retinopathy Study (ETDRS).6 Although laser photocoagulation was effective for some patients in this trial, 12% of treated patients developed visual loss by 3 years after initiation of treatment. In addition, in approximately 40% of treated eyes that had central macular edema at baseline, the central edema persisted at 1 year, and in 25% of treated eyes it persisted at 3 years.

The lack of success in some DME patients (Figure 2) treated with laser photocoagulation has led to the investigation of other therapies. Vitrectomy, with resulting relief of vitreomacular traction, has been shown to resolve macular edema and partially restore visual function in some patients with DME.8,9,10 The surgery is complex and invasive, however, and it may benefit only a subset of patients with DME.

PHARMACOLOGIC APPROACHES
A number of pharmacologic therapies have been investigated for treatment of DME. Some of the most promising approaches involve the inhibition of vascular endothelial growth factor (VEGF), a potent vascular permeability factor.11 VEGF inhibition has been investigated through intravitreal delivery of both corticosteroids and antibodies to VEGF. The two VEGF inhibitors that have been approved in the United States for treatment of AMD, pegaptanib (Macugen; OSI/Eyetech and Pfizer, New York, NY) and ranibizumab (Lucentis; Genentech, San Francisco, CA.), are being investigated in clinical trials for their efficacy and safety in treating DME.12,13

Much attention has been paid lately to these VEGF antibodies for the treatment of retinal diseases, but it should not be forgotten that corticosteroids have also been shown in the laboratory to inhibit the expression of VEGF.14,15 Because of this VEGF-blocking ability, corticosteroids including dexamethasone and triamcinolone acetonide have been investigated as possible treatments for DME.

INTRAVITREAL STERIODS
Intravitreal delivery of corticosteroids can be accomplished by intravitreal injection or by implantation of a sustained-delivery device. This activity concentrates on the intravitreal injection of the steroid triamcinolone acetonide (Kenalog; Bristol-Myers Squibb, New York, NY) for the treatment of DME.

The rationale for the use of triamcinolone in the treatment of DME is the steroid’s ability to attenuate VEGF-mediated vascular permeability. Intravitreal injection places the drug in the posterior segment in close proximity to the target macular tissue. The treatment is easy to perform and inexpensive, and while data from large-scale prospective studies have been lacking, its popularity as a therapeutic option has been driven by promising initial anecdotal reports.

Machemer and colleagues first proposed the intravitreal use of triamcinolone to prevent the formation of proliferative vitreoretinopathy after retinal detachment surgery.16 Following animal studies to establish the safety of commercial triamcinolone acetonide for intravitreal use,17,18 the compound has been used to treat a number of retinal diseases, including AMD.19-21

The use of intravitreal triamcinolone for treating DME was first proposed in 1999 and reported in 2001.22 It was initially used only in patients whose DME was refractory to laser treatment,23 but with promising early results and growing familiarity it is now used by many as a first-line treatment for DME.

The dose generally used by ophthalmologists to treat DME is 4 mg in 0.1 mL.17 With the patient under topical anesthesia in the outpatient setting, the medication is delivered into the vitreous via the pars plana through a 27- to 30-gauge needle.

PUBLISHED DATA
Until recently there have been few published data on the efficacy and safety of triamcinolone for treatment of DME, but now data have begun to emerge from larger case series and from single-center prospective, controlled clinical trials (see A Sampling of Recently Published Experience With Intravitreal Triamcinolone Acetonide in DME).

Martidis and colleagues22 were among the first to report their results with this treatment in a series of 16 eyes with clinically significant DME that had been unresponsive to laser treatment. All eyes completed 3 months’ follow-up, and eight eyes completed 6 months’ follow-up. Central retinal thickness, measured by optical coherence tomography, decreased from baseline by 55% at 1 month, 57.5% at 3 months, and 38% at 6 months, and mean visual acuity improvement was 2.4 lines, 2.4 lines, and 1.3 lines at those same intervals, respectively. Anatomical improvement was seen in 11 of the 16 eyes at 3 months.

Jonas and colleagues reported a series of 26 eyes with visual loss due to DME treated with intravitreal triamcinolone.24 Visual acuity improved in treated eyes from a mean of 20/165 at baseline to a mean of 20/105 at the end of a mean follow-up period of 6.6 months. In a control group of eyes treated with laser, there was no improvement in visual acuity. In 21 patients for whom both pre-injection and post-injection fluorescein angiography were available, leakage decreased after the injection.

UNRESOLVED ISSUES
While these early case series and others subsequently published have been encouraging, there remain some caveats regarding the use of intravitreal triamcinolone acetonide to treat DME.

Adverse events, related to both the injection itself and to the potential toxicity of steroids, have been reported in published cases and case series to date. Events related to injection have included endophthalmitis, retinal detachment, and vitreous hemorrhage. Potential problems related to steroid toxicity include cataractogenesis and the development of glaucoma. In addition, the treatment effect is temporary, and repeated treatments expose the patient each time to the same risks.

There are also issues regarding the use of Kenalog, the commercially available formulation of triamcinolone acetate, for this indication. The drug is formulated for intramuscular or intra-articular use, not for intraocular use.25 Its use for intravitreal injection is “off-label.” Sterile inflammatory reactions after intravitreal injection of triamcinolone have been reported, and these can be difficult to distinguish from bacterial infection.

Over the past year, an increasing number of these sterile inflammatory reactions have been documented, and as a result many clinicians no longer use the commercial formulation of triamcinolone for intravitreal injection. Triamcinolone prepared at a compounding pharmacy is now typically used when it is believed that a corticosteroid injection is indicated. If clinical trials in progress demonstrate that triamcinolone injections for DME are safe and effective, a sterile formulation of triamcinolone acetonide specifically for ophthalmology will be needed, containing no preservatives and no endotoxins.

Another concern related to the use of the commercial formulation of triamcinolone is that the optimal dose for intravitreal use has never been established. The current most commonly used dose, 4 mg in 0.1 mL, was arrived at more out of convenience than through empirical testing. The drug as supplied, 40 mg/mL, can easily be aliquoted into 4 mg/0.1 mL doses, and this volume is small enough to be tolerated in intravitreous injection. No data exist to support the safety or efficacy of this dose over any other, but an ongoing randomized, prospective clinical trial is investigating both a 4- and a 1-mg dose of triamcinolone for DME.26

In light of the potential benefit of intravitreal injection of triamcinolone in the treatment of DME, and the rapid adoption of this therapeutic option by the ophthalmic retina community, reliable evidence of the technique’s safety and efficacy is needed. The Diabetic Retinopathy Clinical Research Network (www.drcr.net) has a number of multicenter controlled clinical trials ongoing to assess the efficacy and safety of intravitreal triamcinolone for DME in comparison to other treatments. In particular, one of the earliest trials undertaken by the DRCR is comparing intravitreal triamcinolone injection with laser photocoagulation;26 that study has completed enrollment and is in the follow-up phase. It is hoped that the results of the study will guide ophthalmologists in the proper use of this emerging treatment for DME.

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