Macular Edema in Diabetes Treatment & Management

As with all complications of diabetes, successful management of macular edema requires good control of the diabetes itself.

The Early Treatment Diabetic Retinopathy Study (ETDRS) was the first study to provide a treatment paradigm in this disease using laser therapy to reduce moderate vision loss in patients with clinically significant macular edema by approximately 50%.^[1] Although prevention of vision loss is important, visual improvement would be preferable.

Over the past few years, research has started to focus on the use to anti–vascular endothelial growth factor (VEGF) therapy to treat diabetic macular edema (DME). As new and promising treatment options emerge and prospective data begin to mount, it is becoming clearer that anti-VEGF therapy will play an increasing role in the treatment of DME.

A variety of intravitreal medications are currently available, with others under study. Pars plana vitrectomy may also be beneficial.

Medical treatment should focus on optimizing glycemic and hypertensive control and lowering lipid levels. Optimal control of diabetes, blood pressure, and lipids has been shown to positively impact diabetic retinopathy.^[7] These issues are best managed by primary care physicians and internists.

Patients should receive follow-up care according to standard practice guidelines. See the American Academy of Ophthalmology Preferred Practice Pattern for Diabetic Retinopathy.

For more information, see the Medscape Reference topics Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, and Diabetic Retinopathy.

Intravitreal triamcinolone acetonide

Intravitreal triamcinolone acetonide (IVTA) has been shown to significantly reduce macular edema and to improve visual acuity, particularly when the macular edema is pronounced.^{[8, 9, 10]} Action is maximal at 1 week, lasting 3-6 months.

Some studies advocate IVTA as primary therapy, whereas others label it as adjunctive therapy to macular photocoagulation.^[11]

Patients should be counseled about the risk (30-40%) of increased intraocular pressure, which usually can be medically controlled. Other adverse effects include a less than 1% chance of retinal detachment, cataract, and endophthalmitis.

Intravitreal anti-VEGF agents

Vascular endothelial growth factor (VEGF) increases retinal vascular permeability, causes breakdown of the blood-retina barrier, and results in retina edema. VEGF is up-regulated in diabetic retinopathy. Three currently available anti-VEGF agents are pegaptanib sodium, ranibizumab, and bevacizumab.

Pegaptanib sodium is a pegylated aptamer directed against the VEGF-A₁₆₅ isoform. It was the first FDA-approved ophthalmologic anti-VEGF agent for the treatment of choroidal neovascularization (CNV) from age-related macular degeneration (ARMD). In a phase 2 prospective clinical trial, it appeared to improve anatomic and visual outcome in patients with diabetic macular edema.^[12] Phase 3 trials of pegaptanib sodium for diabetic macular edema are being conducted.

Ranibizumab is a recombinant humanized antibody fragment that is active against all isoforms of VEGF-A. Intravitreal ranibizumab is FDA approved for the treatment of exudative ARMD. In the RESOLVE study (phase 2, placebo-controlled, randomized, multicenter study), 151 patients were randomized 1:1:1 to ranibizumab monotherapy at a dose of 0.3 mg or 0.5 mg or sham treatment. Rescue laser photocoagulation treatment was offered with persistent disease activity after 3 months. Patients received an initial treatment of 3 consecutive monthly injections and were followed monthly with an as-necessary regimen from month 3 to month 12. At month 12, a mean increase in best corrected visual acuity (BCVA) of 11.8 letters in the 0.3-mg group and of 8.8 letters in the 0.5-mg group was noted, as compared with a reduction in BCVA of -1.4 letters in the sham group.^[13]

In the READ-2 study (phase 2, randomized multicenter study), 126 patients were randomized 1:1:1 to receive 0.5 mg of ranibizumab, focal/grid laser coagulation, or a combination of ranibizumab and laser. At month 6, the mean gain in BCVA was significantly greater in the ranibizumab monotherapy group, with +7.2 letters, compared with the laser monotherapy group, who lost -0.4 letters and the combination treatment group, gaining only +3.8 letters.^[14]

In the RESTORE study (phase 3, laser-controlled, randomized, multicenter study), 345 patients were randomized 1:1:1 to 0.5 mg ranibizumab plus sham laser, 0.5 mg ranibizumab plus active laser, or sham injections with active laser. A treatment initiation phase included 3 consecutive monthly intravitreal injections of either ranibizumab or sham. Subsequently, an as-necessary regimen was followed from month 3 to month 12. The mean change in BCVA from baseline to months 1-12 was +6.1 letters in the ranibizumab monotherapy group, +5.9 letters in the group receiving combination therapy with ranibizumab and laser, and +0.8 letters in the laser alone group.^[15]

The Diabetic Retinopathy Clinical Research Network performed a phase 3 randomized multicenter trial randomizing 854 eyes to sham injection plus prompt laser, ranibizumab injection plus prompt laser, ranibizumab injection plus deferred laser, or 4-mg triamcinolone injection plus prompt laser. The 1-year mean change in BCVA was significantly greater in the group receiving ranibizumab plus prompt/deferred laser, with +9 letters, compared with triamcinolone or sham treatment plus laser, with +4 and +3 letters, respectively. In pseudophakic eyes, intravitreal triamcinolone injection plus prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.^[16] The expanded 2-year results are similar to the 1-year results and reinforce the conclusion that ranibizumab should be considered for patients with diabetic macular edema.^[17]

Bevacizumab is a full-length recombinant humanized antibody that is active against all isoforms of VEGF-A. It is FDA approved as an adjunctive systemic treatment for metastatic colorectal cancer. Small, nonrandomized pilot studies have documented some efficacy against diffuse diabetic macular edema. The Diabetic Retinopathy Clinical Research Network conducted a phase 2, prospective, randomized, multicenter clinical trial to determine the safety and possible benefits of this agent. They concluded that intravitreal bevacizumab can reduce diabetic macular edema in some eyes, but the study was not designed to determine whether the treatment was beneficial.^[12] A phase 3 trial would be needed for that purpose.

The intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT) study also recently released 12-month data. This is a prospective, single-center, randomized, 2-year trial, enrolling 80 patients with center-involving clinically significant macular edema (CSME) who had received at least 1 prior macular laser treatment, to compare the efficacy of repeated intravitreal bevacizumab with 4 monthly modified macular laser treatments. The mean change in ETDRS visual acuity at 12 months in the laser group was -0.5 letters, while the bevacizumab group gained a mean of 8 letters during the same period.^[18]

Laser photocoagulation is a well-proven therapy to reduce the risk of vision loss from diabetic macular edema. The Diabetic Retinopathy Clinical Research Network reported results from a multicenter, randomized clinical trial comparing focal/grid laser photocoagulation and intravitreal triamcinolone for the treatment of diabetic macular edema. They concluded that over a 2-year period, focal/grid laser photocoagulation is more effective and has fewer adverse effects than 1- or 4-mg doses of preservative-free intravitreal triamcinolone for most patients with diabetic macular edema.^[20]

Studies on all other surgical modalities have been limited in the number of patients and the scope of disease being treated; therefore, these procedures have limited use and questionable efficacy.

The goal of macular laser treatment is to reduce progression of diabetic macular edema; significant visual improvement is uncommon. Photocoagulation has been shown to reduce the risk of moderate visual loss from diabetic macular edema by 50%, from 24% to 12%, 3 years after initiation of treatment.^[1]

Laser treatment is most effective when initiated before visual acuity is lost from diabetic macular edema; this emphasizes the need for diligent monitoring and follow-up care.

Laser treatment of diabetic macular edema should precede panretinal photocoagulation (PRP) by at least 6 weeks because the use of PRP before laser treatment may worsen diabetic macular edema. PRP should not be delayed in patients with very severe nonproliferative diabetic retinopathy or high-risk proliferative diabetic retinopathy.

Laser treatment is directed toward areas of leakage that have been identified by examination (areas of retinal thickening) or by fluorescein angiography. The laser produces burns 50-100 µm in diameter. Focal treatment addresses leaking microaneurysms. Grid pattern photocoagulation is used for diffuse leakage. Argon green, krypton yellow, and 532 frequency up-converted diode lasers are used to treat focal lesions. Scatter laser photocoagulation involves placement of multiple argon blue-green or green or krypton red laser burns.

Lesions amenable to laser treatment include the following:

• Focal leaks greater than 500 µm from the foveal center that are believed to cause retinal thickening or hard exudates
• Focal leaks 300-500 µm from the foveal center that are causing retinal thickening and hard exudates and have persisted after a first treatment in a patient with visual acuity of less than 20/40, provided that treatment will not destroy the perifoveal capillary network
• Areas of diffuse leakage: microaneurysms, intraretinal microvascular abnormality (IRMA), or diffusely leaking macular capillary bed
• Thickened avascular zones, other than the normal foveal avascular zone

It is important to avoid the foveal avascular zone.

VEGF Trap-Eye is a soluble VEGF receptor fusion protein that binds all forms of VEGF-A and related placental growth factor (PGF). When administered as a single 4 mg intravitreal injection in a phase 1 study, a marked decrease in central retinal thickness and mean macular volume was noted.

The phase 3 FAME (fluocinolone acetonide in diabetic macular edema) trial is evaluating the Alimera fluocinolone-based injectable implant.

The phase 3 trial of Posurdex biodegradable implant (sustained delivery formulation of dexamethasone) for the treatment of diabetic macular edema is under way.

Retisert,^[19] another steroid implant (fluocinolone acetonide), was evaluated in patients with diabetic macular edema with good results, but its adverse effect profile was cause for concern (90% of patients developed cataracts, and 40% required glaucoma surgery within 3 y).

Many studies suggest that vitreomacular traction or the vitreous itself may play a role in increased retinal vascular permeability.^{[21, 22]} Removal of the vitreous or relief of vitreous traction with vitrectomy may, in some patients, be followed by resolution of macular edema and corresponding visual rehabilitation. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema.

Patients with refractory clinically significant macular edema (CSME) and a taut posterior hyaloid face who have not responded to macular laser treatment may benefit from a vitrectomy, with possible significant improvement in visual acuity.^[21]

In eyes with diffuse diabetic macular edema without posterior vitreous detachment, vitrectomy with posterior vitreous detachment may be effective in resolving the diabetic macular edema and may lead to an increase in visual acuity.^[22]

Adverse effects and complications of laser use are related mostly to either misdirected light or excessive energy, both of which are generally preventable with operator familiarity with standard treatment parameters.

Subretinal fibrosis is a vision-threatening condition, which occurred in 2% of eyes with diabetic macular edema in the Early Treatment Diabetic Retinopathy Study (ETDRS).^[23] Subretinal fibrosis is an elevated mound or flat sheet of grey or white tissue deep to the retina at or near the center of the macula. On fluorescein angiography, this lesion is hyperfluorescent in the capillary phase with persistence into the late phase and diffusion of dye. Subretinal fibrosis is associated most strongly with very severe hard exudates. It also is associated with a poor lipid profile. A previously proposed association with laser treatment has not been demonstrated in studies. The prognosis for patients with this complication is poor; subretinal fibrosis is generally refractive to focal laser therapy.

Residual massive foveal hard exudates may remain after the resolution of diabetic macular edema and may be associated with profound and irreversible vision loss. In one study, aspiration of hard exudates following a small retinotomy and serous neurosensory detachment resulted in an increase of visual acuity in 5 of 7 patients.^[24]