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%. ^[6] Although prevention of vision loss is important, visual improvement would be preferable.

Research has started to focus on the use of 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 corticosteroids

Triamcinolone acetonide

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

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

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

Dexamethasone

In July 2014, the FDA approved dexamethasone intravitreal implant (Ozurdex) for diabetic macular edema in patients who are pseudophakic or who are phakic and scheduled for cataract surgery. ^[12] This indication was expanded to include the general DME patient population in September 2014. ^[13] Approval was based on two randomized, multicenter, masked, placebo-controlled, phase 3 clinical trials with identical protocols. Data from 1048 patients were pooled for analysis. The percentage of patients with ≥15-letter improvement in best-corrected visual acuity (BCVA) from baseline was greater with dexamethasone intravitreal implant 0.7 mg (22.2%) than with placebo implant (12%). ^[14]

Fluocinolone acetonide

The FDA approved a long-acting fluocinolone intravitreal implant (Iluvien) in September 2014 for the treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. Iluvien consists of a tiny, cylindrical tube containing fluocinolone acetonide that is implanted in the back of the eye via a 25-gauge needle and that releases submicrogram levels of the drug for 36 months. Possible adverse reactions to the implant include increased ocular pressure and cataract development. ^[15]

Approval was based on clinical trial data from the Fluocinolone Acetonide for Macular Edema (FAME) studies that showed that, at Month 24 after receiving the fluocinolone implant (releases 0.2 mcg/day), 28.7% of patients (P = 0.002) experienced an improvement from baseline in their best corrected visual acuity of 15 letters or more on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart. Patients treated with the implant experienced a statistically significant improvement in visual acuity compared with the control group by Week 3 of follow-up and maintained a statistically significant advantage over the control through completion of the trial at Month 36. ^[16]

Intravitreal anti-VEGF agents

Vascular endothelial growth factor (VEGF) increases retinal vascular permeability, causes breakdown of the blood-retina barrier, and results in retinal edema. VEGF is up-regulated in diabetic retinopathy. Currently available anti-VEGF agents in the United States include faricimab, pegaptanib sodium, ranibizumab, aflibercept, and bevacizumab. Bevacizumab is not commercially available as an intravitreal injection. 

Faricimab

Faricimab is the first bispecific antibody for treatment of adults with DME. Faricimab targets two distinct pathways – angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). By inhibiting VEGF-A, faricimab suppresses endothelial cell proliferation, neovascularization, and vascular permeability. By inhibiting Ang-2, faricimab promotes vascular stability and desensitizes blood vessels to the effects of VEGF-A. Ang-2 levels are increased in some patients with DME. 

Approval was based on the phase 3 YOSEMITE and RHINE studies conducted in 353 worldwide sites. The studies randomized adults with vision loss due to center-involving diabetic macular edema to receive intravitreal faricimab 6 mg every 8 weeks, faricimab 6 mg per personalized treatment interval (PTI), or aflibercept 2 mg every 8 weeks up to Week 100. The primary endpoint was mean change in best-corrected visual acuity at 1 year. Patients were randomly assigned to faricimab every 8 weeks (YOSEMITE, n=315; RHINE, n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Vision gains and anatomic improvements with faricimab were achieved with adjustable dosing up to every 16 weeks. ^[17]

Pegaptanib

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. ^[18] Phase 3 trials of pegaptanib sodium for diabetic macular edema are being conducted. 

Ranibizumab

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 randomly assigned in a 1:1:1 ratio to receive 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 three 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. ^[19]

In the READ-2 study (phase 2, randomized multicenter study), 126 patients were randomly assigned in a 1:1:1 ratio 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, which only gained +3.8 letters. ^[20]

In the RESTORE study (phase 3, laser-controlled, randomized, multicenter study), 345 patients were randomly assigned in a 1:1:1 ratio to receive 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 three 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 to 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. ^[21]

The Diabetic Retinopathy Clinical Research Network performed a phase 3 randomized multicenter trial randomly assigning 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. ^[22] 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. ^[23]

Three-year results of this trial were reported in 2012, suggesting that focal/grid laser treatment at the initiation of intravitreal ranibizumab is not better, and may be worse, for vision outcomes than deferring laser treatment for at least 24 weeks in patients with DME involving the fovea and with vision impairment. ^[24]

The FDA approved ranibizumab (Lucentis) for diabetic macular edema in August 2012. Approval was based on the phase 3 trials, RIDE and RISE, two identically designed, parallel, double-blind, 3-year clinical trials, which were placebo-treatment–controlled for 24 months. A total of 759 patients were randomly assigned into three groups to receive monthly treatment with 0.3 mg ranibizumab (n=250), 0.5 mg ranibizumab (n=252), or placebo injection (control group, n=257). Results showed participants who received 0.3 mg ranibizumab experienced significant, early (Day 7), and sustained (24 months) improvements in vision (P< .01). ^[25]

The following are results from the RIDE and RISE trials:

• More patients who received ranibizumab were able to read at least three additional lines (15 letters) on the eye chart at 24 months (RIDE, 34% in the 0.3-mg group vs 12% in the control group; RISE, 45% in the 0.3-mg group vs 18% in the control group)

• The ranibizumab group had average vision gains exceeding two lines (10 letters) on the eye chart at 24 months (RIDE, 10.9 letters in the 0.3-mg group vs 2.3 letters in the control group; RISE, 12.5 letters in the 0.3-mg group vs 2.6 letters in the control group)

• Significant gains in average vision were observed 7 days after the first treatment

• The ranibizumab group was significantly more likely to maintain their vision (lose < 15 letters on the eye chart) at 24 months (RIDE, 98% in the 0.3-mg group vs 92% in the control group; RISE, 98% in the 0.3-mg group vs 90% in the control group)

• Vision improvements observed with ranibizumab treatment at 24 months were maintained with continued treatment through 36 months 

In 2018, the DRCR Network completed Protocol U, a short term study comparing the addition of a dexamethasone implant (Ozurdex) to ranibizumab (Lucentis) in patients who have continued diabetic macular edema. They concluded that simultaneous administration of corticosteroids with ranibizumab decreased retinal thickness on OCT at 6 months, but the addition of steroid did not yield better VA results than ranibizumab alone. ^[26]  

Aflibercept 

The FDA approved aflibercept for diabetic macular edema in August 2014. It was previously approved for neovascular age-related macular degeneration and macular edema. Approval for DME was based on two studies (VISTA and VIVID) comparing aflibercept with macular laser photocoagulation, in which patients treated with aflibercept were able to read, on average, two additional lines on an eye chart, whereas patients in the control group showed no improvement. ^[27]

Bevacizumab

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. Intravitreal bevacizumab reduced diabetic macular edema in some eyes, but the study was not designed to determine whether the treatment was beneficial. ^[18] 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 one prior macular laser treatment, to compare the efficacy of repeated intravitreal bevacizumab with four monthly modified macular laser treatments. The mean change in ETDRS visual acuity at 12 months in the laser group was -0.5 letters, whereas the bevacizumab group gained a mean of eight letters during the same period. ^[28] At 24 months the mean change in ETDRS visual acuity was a gain of 8.6 letters for the bevacizumab group compared with a mean loss of 0.5 letters for the macular laser therapy group. ^[29]

In 2015, the Diabetic Retinopathy Clinical Research (DRCR) Network reported the results of a randomized clinical trial to compare relative changes in visual acuity following 1 year of intravitreal injections of anti-VEGF agents aflibercept, bevacizumab, and ranibizumab for the treatment of diabetic macular edema involving the center of the macula (Protocol T). The mean change in visual acuity at 1 year was greater with aflibercept (+13.3) than bevacizumab (+9.7) or ranibizumab (+11.2). However, this was not clinically significant.

The greater overall effect was driven by eyes with initial visual acuity of 20/50 or worse. Mean visual acuity letter score improvement in this subgroup was +18.9 for aflibercept, +11.8 for bevacizumab, and +14.2 for ranibizumab (P values: aflibercept-bevacizumab, < 0.001; aflibercept-ranibizumab = 0.003; ranibizumab-bevacizumab = 0.21). For eyes with an initial visual acuity of 20/32 to 20/40, the mean change was +8.0 for aflibercept, +7.5 for bevacizumab, and +8.3 for ranibizumab (P values: >0.50 for each pairwise comparison).

In conclusion, in eyes with decreased visual acuity due to diabetic macular edema, all three agents, on average, substantially improved VA. However, the relative effect depends on initial visual acuity. When initial visual acuity loss was mild, there were no apparent differences among the three treatment groups. However, the worse the initial visual acuity, the greater the relative advantage of aflibercept over the other two agents. ^[30]

In 2016, the DRCR Network reported the 2-year results of Protocol T. Overall, at 2 years, aflibercept improved vision more than bevacizumab, but a difference between ranibizumab and aflibercept in terms of outcome was not identified. In eyes with baseline vision of 20/32 to 20/40, all three agents improved vision similarly. However, in eyes with baseline vision of 20/50 or more, the benefit of aflibercept over ranibizumab was no longer statistically significantly different, whereas bevacizumab remained inferior. ^[31]

In 2019, the DRCR Network reported the results of Protocol V in which adults with type 1 or 2 diabetes who had central-involved diabetic macular edema (CI-DME) and Snellen equivalent BCVA of 20/25 or better were randomized to initial management with aflibercept, focal/grid laser, or observation with aflibercept given in the laser and observation groups if VA decerased from baseline. At 2 years, there was no difference in VA loss between the three study arms, and mean VA was 20/20 in all groups. Based on these results, many clinicians and patients might choose initial observation for eyes with CI-DME and good VA, withholding anti-VEGF treatment unless VA worsens. ^[32]

 

Laser photocoagulation is a well-proven therapy to reduce the risk for 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. ^[33]

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 for moderate visual loss from diabetic macular edema by 50%, from 24% to 12%, 3 years after initiation of treatment. ^[6]

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.

Macular thickness and the need for retreatment

In patients with diabetic macular edema, a significant association exists between higher central macular thickness at baseline and the need for at least three treatments with a combination of IVTA and laser photocoagulation, according to a study by O’Day et al. In a post-hoc analysis derived from a prospective, randomized, double-blind, placebo-controlled trial (42 patients/42 eyes), the investigators found that half of the study’s patients required three or more IVTA/laser treatments, with macular thickness being the only baseline characteristic significantly associated with the number of treatments received. ^[34]

Day and colleagues suggested that as a result of requiring more treatments, patients with high baseline thickness may be at greater risk for intraocular pressure increase, progression of cataract, and steroid-associated adverse events.

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.

Retisert, ^[35] a 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. ^{[36, 37]} 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. ^[36]

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. ^[37]

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). ^[38] 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 five of seven patients. ^[39]