If you are diagnosed with diabetic macular edema, there are a number of treatment options. Work with an eye care specialist experienced in managing DME to identify the best treatment for you.

Know your options! As a DME patient, you can take accountability of your condition.

A major development in treating vision loss in people with DME has been the introduction of anti-VEGF drugs, which leverage recent advances in our understanding of the different mechanisms that cause DME. These drugs are designed to attack specific factors that contribute to DME development and are improving our ability to treat this condition.

Anti-VEGF agents target and block the glycoprotein VEGF (vascular endothelial growth factor). In DME, VEGF is produced at higher than normal amounts in the retina. Lowering levels of VEGF with anti-VEGF drugs reduces its effects on retinal blood vessels, prompting a reduction in macular edema without risk of developing other major eye conditions.⁷⁰

There are three major responses to anti-VEGF therapy:

• 1) Reduced vascular permeability^{28, 61}
• 2) Decreased thickening of the macula and retina^{33, 61}
• 3) Improved visual acuity^{33, 61, 64}

Once the over-expression of VEGF is halted, its effects subside and leaking blood vessels diminish, reducing DME.

Anti-VEGF therapy is the preferred treatment and clinical trials have demonstrated that it is more effective in reducing DME and improving vision than corticosteroid therapy⁶⁴ or laser photocoagulation⁷⁰ without causing complications associated with the former treatments.^{71, 72} However, responses can vary greatly among patients and combination therapy may be appropriate for some patients.⁶⁹ A major study showed that combining anti-VEGF and laser therapies could have long-term benefits in reducing edema and requiring less frequent injections.^{64, 73} Combining corticosteroid therapy with anti-VEGF treatment did not demonstrate additional benefit to anti-VEGF treatment alone.⁶⁴

The advent of anti-VEGF therapy has revolutionized treatment of DME and offers patients new promise for maintaining a higher quality of life. Currently two agents, ranibizumab (Lucentis) and aflibercept (Eylea), are approved to treat DME in the United States^111,112 and the European Union.^113,114 Trials are ongoing and further data is needed to understand the role and limitations of other agents. Strategies for managing DME will continue to evolve as more data is collected from these trials.

Lucentis

Lucentis (ranibizumab) is the first anti-VEGF drug to be approved for treatment of DME. It is injected directly into the eye at a recommended monthly dose of 0.3 mg in the US and 0.5 mg in the EU, and can stabilize or even improve vision in DME patients. In 2015, the approved use for Lucentis was expanded to treat diabetic retinopathy (DR) in patients with diabetic macular edema (DME). Lucentis has also been approved for treatment of other eye diseases including wet age-related macular degeneration (wet AMD) central retinal vein occlusion (CRVO), and myopic choroidal neovascularization (myopic CNV).

Data from the phase III RISE and RIDE clinical trials, involving more than 750 patients, have shown that after two years of treatment, monthly injections of
0.3 mg of Lucentis significantly improved vision for 34% to 45% of patients, with gains of at least 15 letters in visual acuity, and helped to prevent further vision loss.⁹⁸ Lucentis treatment also reduced central retinal thickness and occurrence of side effects was rare.⁹⁸

The phase III study RESTORE involved 345 patients with visual impairment due to DME and demonstrated that 0.5 mg of Lucentis injections alone and in combination with laser improve vision and reduce macular edema far greater than laser therapy alone.¹⁰² After 12 months of treatment, visual acuity improved by at least 15 letters for 23% of patients receiving Lucentis injections compared to only 8.2% of patients receiving laser therapy alone.¹⁰²

These positive results prompted an extension of the RESTORE study for a second year in the phase IIIb trial, which involved 220 patients and demonstrated that benefits gained in vision in the first 12 months were maintained at 24 months.¹⁰³ Central retinal thickness also reduced in patients receiving 0.5 mg of Lucentis injections far greater than those receiving laser alone.¹⁰³

Most common side effects over 2 years were nasopharyngitis, eye pain, hypertension and cataract. No new safety issues occurred between the first and second year of treatment.¹⁰³

Commonly reported ocular side effects of Lucentis injections include conjunctival hemorrhage, cataract, increased intraocular pressure, and vitreous detachment. ^{98, 99}

Eylea
 

Eylea (aflibercept) is the second anti-VEGF drug to be approved for treatment of DME and can stabilize or even improve vision in DME patients. It is injected directly into the eye at a recommended dose of 2 mg every 8 weeks following five initial monthly (4 weeks) injections.¹¹⁵ In 2015, the approved use for Eylea was expanded to treat diabetic retinopathy (DR) in patients with diabetic macular edema (DME). Eylea has also been approved for treatment of other eye diseases, including wet age-related macular degeneration (wet AMD) central retinal vein occlusion (CRVO), and myopic choroidal neovascularization (myopic CNV).
 

Eylea’s approval for the treatment of DME was based on the 12-month results from the phase 3 VIVID-DME and VISTA-DME clinical trials, which demonstrated that Eylea injections improve and stabilize vision more effectively than laser therapy. These trials involved 862 participants who received either 2 mg of Eylea monthly, 2 mg of Eylea every two months after 5 initial monthly injections, or laser therapy alone.
 

After 12 months of treatment, patients in the VISTA-DME trial receiving 2 mg of Eylea monthly had a mean change in visual acuity of 12.5 letters, compared to 10.7 letters for those receiving 2 mg every two months (after 5 initial monthly injections), and 0.2 letters for those receiving laser.¹¹⁶ Visual acuity improved by at least 15 letters for 41.6% of patients receiving monthly Eylea injections, compared to 31.1% of the patients receiving Eylea every 2 months (after 5 initial monthly injections), and 7.8% of patients receiving laser. Central retinal thickness also reduced far greater in patients receiving either dosing regiment of Eylea injections than those receiving laser.
 

In the VIVID-DME trial, patients receiving 2 mg of Eylea monthly had a mean change in visual acuity of 10.5 letters compared to 10.7 letters for those receiving Eylea every two months (after 5 initial monthly injections), and 1.2 letters for those receiving laser. Visual acuity improved by at least 15 letters for 32.4% of the patients receiving monthly Eylea injections, 33.3% of patients receiving Eylea every 2 months (after 5 initial monthly injections), and 9.1% of those receiving laser. Central retinal thickness also reduced far greater in patients receiving either dosing regimen of Eylea injections than those receiving laser.
 

The VISTA-DME and VIVID-DME studies are ongoing for a total of three years.
 

Commonly reported ocular side effects of Eylea in DME clinical trials include conjunctival hemorrhage, eye pain, ocular hyperemia and vitreous floaters.
 

DRCR.net Protocol T

 
The Diabetic Retinopathy Clinical Research Network completed a 1-year head-to-head comparison trial of ranibizumab, bevacizumab, and aflibercept. The results of the Protocol T study, involving 660 participants, demonstrated that aflibercept, bevacizumab, and ranibizumab are all effective and relatively safe treatments for DME, with little difference between the drugs with baseline visual acuity 20/40 or better. The data did show, however, that at a baseline visual acuity of 20/50 or worse, aflibercept is the more effective treatment at improving vision. As the study noted, “at worse initial levels of vision, aflibercept had a clinically meaningful advantage; for example, an improvement in the visual-acuity letter score of at least 15 (3 snellen lines) was observed in 63% more aflibercept-treated eyes than bevacizumab-treated eyes (67% vs. 41%) and in 34% more aflibercept-treated eyes than ranibizumab-treated eyes (67% vs. 50%).”
 
The mean change in central subfield thickness (CST) from baseline was greater with aflibercept compared to the other agents, regardless of baseline visual acuity, and the reductions in CST with aflibercept were significantly greater compared to bevacizumab. On average, subfield thickness decreased by 169 μm with aflibercept, 101 μm with bevacizumab, and 147 μm with ranibizumab. Laser photocoagulation was performed in fewer aflibercept-treated eyes compared to eyes treated with the other agents, which may reflect the greater proportion of aflibercept-treated patients with resolution of central-subfield involved diabetic macular edema.
 
Retina specialists disagree about how to interpret Protocol T, the first direct head-to-head comparison study of the anti-VEGF agents in use today. The study’s findings indicate that aflibercept may be a better choice for patients with vision that is 20/50 or worse, but for patients with mild vision loss, the findings suggest that all three agents are similarly effective and 75% of patients with DME present have a baseline VA of 20/40 or better. Affordability may therefore become an important factor in treatment decisions.
 
It is important to note that the bevacizumab used in Protocol T was not in a form that is readily available to clinicians. Thus, the findings may not reflect a true head-to-head comparison of the three drugs.
 
References:
 
The Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. N Engl J Med. 2015;372:1193-1203;
Martin DF, Maguire MG. Treatment choice for diabetic macular edema. N Engl J Med. 2015;372:1260-1261.

Focal laser photocoagulation, also known as focal laser treatment, has been until recently the standard treatment for DME.⁶ It stabilizes vision and can prevent vision loss caused by DME,¹⁶ but rarely improves visual acuity.^{15, 16, 62} Laser therapy has not been effective in most patients with diffuse DME.²⁴ This underscores the importance of screening for DME and diabetic retinopathy before experiencing any symptoms.

Until recently, focal laser treatment had been the standard treatment for DME.⁶

During laser photocoagulation, areas of leakage in the retina are exposed to small laser burns that decrease the quantity of fluid and slow down leakage. This treatment is usually completed in one session but some cases require multiple procedures. If you have DME in both eyes, laser therapy will be applied to one eye at a time, with procedures typically separated by several weeks.¹⁵

Laser therapy is not always effective. Safety issues include possible discomfort during the procedure and potential damage or scarring to the retina.⁶³

If too much blood has leaked into the vitreous or the retina has detached from the eye, your doctor may recommend getting a vitrectomy.¹³ Vitrectomy is a procedure in which the vitreous is replaced with a salt solution, improving the visual acuity and maintaining the anatomy of the eye.⁶⁸ Vitrectomy has been very successful with restoring sight by removing blood, but it is not as effective for re-attaching the retina.¹³
 

Corticosteroids work by targeting two of the different mechanisms that cause the disease: inflammation (or swelling) and VEGF expression.⁶⁴

There is a substantial amount of evidence that inflammation and expression of the growth factor VEGF contribute to the development of DME.^{6, 64, 65} Steroids are anti-inflammatory and can interfere with the mechanisms that cause inflammation⁶ within blood vessels. Additionally, steroids suppress VEGF-expression and, in so doing, prevent damage to the blood vessels and growth of abnormal vessels.⁶⁴

Corticosteroids can be delivered by intravitreal injection⁶⁶ or by sustained release implants.⁹⁵ Implants may have the benefit of less frequent dosing than injections.⁶

Corticosteroid therapy has been found to have greater short-term benefit than laser treatment, in terms of visual acuity gain. However, their benefit declines after several months and ultimately becomes inferior to laser by the second and third year. Treatment that combines corticosteroid and laser therapies also has greater short-term results than corticosteroid therapy alone, but those benefits decline in the long-term and ultimately match those of steroid treatment alone.⁶

Corticosteroid therapy may cause other eye complications such as cataracts or an increase in intraocular pressure, which is a major risk factor for glaucoma.⁶⁷ Studies found higher rates of complications from the combination treatment than corticosteroid therapy alone.^{6, 64, 66} Sustained release implants have been found to cause similar side effects⁶⁶.

Ozurdex

Ozurdex is a sustained-release, biodegradable corticosteroid implant that was recently approved for treatment of DME in the United States for adults who have an artificial lens implant (pseudophakic) or who are scheduled for cataract surgery (phakic),¹¹⁷ and in the European Union for pseudophakic patients and for those who do not benefit from non-corticosteroid therapy.¹¹⁸ The implant, which contains 0.7 mg of the dexamethasone, is injected into the vitreous of the eye and gradually releases medicine over time. Ozurdex has also been approved for the treatment of other eye diseases called branch or central retinal vein occlusion (BRVO or CRVO) and non-infectious uveitis affecting the posterior segment of the eye.¹¹⁹

Ozurdex can help stabilize vision in DME patients without the need for monthly anti-VEGF injections.¹²⁰

Commonly reported side effects of Ozurdex in DME clinical trials include cataract, increased eye pressure, and conjunctival hemorrhage.¹²¹
 

Iluvien
 

Iluvien is a sustained-release, non-erodible, corticosteroid implant that is approved in the United States¹²⁷, Austria, Denmark, France, Germany, Italy, Norway, Portugal, Spain, Sweden and the United Kingdom¹²² for treating vision impairment associated with chronic DME considered insufficiently responsive to available therapies.¹²³ The implant, which contains 0.00023 mg of fluocinolone acetonide (FA), is injected into the vitreous of the eye and is designed to release the medicine gradually for up to three years.¹²⁴

Iluvien can help stabilize or even improve vision in DME patients without the need for monthly anti-VEGF injections.¹²⁵

Commonly reported side effects of Iluvien in DME clinical trials include cataract development and increased ocular pressure.¹²⁶

There is a growing need for effective management of DME as the population ages and prevalence of DME increases.²² Clinical studies to investigate the role of different anti-VEGF agents for treating DME are ongoing. The duration and combination of therapies is also being studied. Further research is needed to better understand the role of other risk factors in DME development¹⁹ and to improve the ability to predict one’s risk for developing DME,⁷⁴ which would inform public health programs and help prevent new cases of DME. There is also a need to understand better the role of combining anti-VEGF and laser therapies.⁶² Further research on whether anti-VEGF treatment outcomes differ by focal or diffuse DME type would help to improve patient care. Finally, future studies that identify the adverse effects and toxicities of anti-VEGF therapy are still needed.⁷⁵

Such developments hold significant promise for providing each DME patient with the most effective treatment and greatly improving patient quality of life.