Modern Approaches to the Treatment of DME

With a suggested protocol that has proven effective.

Ratomir Lazic, MD, PhD • Marko Lukic, MD • Nikica Gabric, MD, PhD

For the past several years, the approach to the treatment of diabetic macular edema has dramatically changed. DME, a common clinical manifestation of diabetic retinopathy, is one of the main causes of impaired vision. Retina specialists are required to find the fastest, most effective, most cost-efficient way to treat DME in their patients.

The thickening of the basement membrane and the reduction in the number of pericytes are believed to lead to increased permeability and incompetence of the retinal vasculature.¹ The compromised blood-retinal barrier allows the leakage of plasma constituents into the surrounding retina, subsequently leading to retinal edema.¹ The result of this pathomechanism is oxidative stress and hypoxia, followed by VEGF production.

Funatsu et al. showed that inflammatory factors, including intercellular adhesion molecule (ICAM)-1, interleukin (IL)-6, and monocyte chemotactic protein (MCP)-1, play roles in the pathology of DR and DME.² The presence of these inflammatory factors in DR suggests that chronic inflammation is involved in the pathogenesis of the disease as well. These molecular findings have resulted in the development of new drugs that are more effective in the treatment of DME, compared to laser.

INSULIN CONTROL AND LASER

The Diabetes Control and Complications Trial (DCCT) revealed the importance of adequate blood sugar regulation in patients with type 1 diabetes. Long-term microvascular changes cause the clinical manifestations seen in DR patients, and intensive blood sugar control, maintained as close to normal as possible, using an insulin pump or three daily doses of insulin, reduced the risk of DR development by 76%, compared to conventional treatment. Intensive therapy slowed the progression of retinopathy by 54% and reduced the development of proliferative or severe nonproliferative diabetic retinopathy by 47%.³

Provided that careful follow-up can be maintained, scatter photocoagulation is not recommended for eyes with mild or moderate nonproliferative DR. When retinopathy is more severe, scatter photocoagulation should be considered and usually should not be delayed if the eye has reached the high-risk proliferative stage.

The Early Treatment Diabetic Retinopathy Study (ETDRS) was the first relevant clinical study regarding the benefit of laser photocoagulation in patients with DR. This four-year, multicenter, randomized study included 3,711 patients with mild to severe nonproliferative DR or mild proliferative DR, in which different kinds of laser treatments were investigated.⁴

The ETDRS results demonstrated that, for eyes with macular edema, focal photocoagulation was effective in reducing the risk of moderate visual loss, but scatter photocoagulation was not. Focal treatment also increased the chances of visual improvement, decreased the frequency of persistent macular edema, and caused only minor visual field loss. Focal treatment should be considered for eyes with macular edema that involves or threatens the center of the macula.⁴

PHARMACOTHERAPY Anti-VEGF Agents

The Diabetic Retinopathy Clinical Research Network's trial of ranibizumab helped us to understand the importance of pharmacotherapy and its efficiency when compared to laser treatment.⁵ In a multicenter, randomized, clinical trial, patients were divided into four groups:

(1) sham injection + prompt laser
(2) 0.5 mg ranibizumab + prompt laser (within 10 days after ranibizumab application)
(3) 0.5 mg ranibizumab + deferred laser (within 24 weeks after ranibizumab application)
(4) 4.0 mg triamcinolone acetonide + prompt laser.

The one-year results showed significantly increased mean BCVA from baseline in both ranibizumab groups (+9 ±11 letters, P <.001 in the ranibizumab + prompt laser group and +9 ±12 letters, P <.01 in the ranibizumab + deferred laser group). Mean BCVA in triamcinolone + prompt laser group was +4 ±13 letters (P = .31). Subgroup analysis showed that mean BCVA in pseudophakic eyes in the triamcinolone + prompt laser group was similar to the ranibizumab + laser groups.⁵

The RESOLVE study was a 12-month, multicenter, sham-controlled, double-masked study with eyes randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections groups.⁶ The patients were given three consecutive monthly injections, followed by PRN injections over a 12-month follow-up. Rescue laser could be performed if needed. At 12 months, mean BCVA was significantly better compared to sham (10.3 ±9.1 letters).

The RESTORE study involved two ranibizumab groups (ranibizumab + sham laser and ranibizumab + laser) and a laser + sham injections group. The results were presented 12 months after baseline. Ranibizumab alone or combined with laser was superior to laser monotherapy.⁷

Five groups were investigated in DRCR.net's trial of bevacizumab: focal photocoagulation at baseline; intravitreal injection of 1.25 mg bevacizumab at baseline and at six weeks; intravitreal injection of 2.5 mg bevacizumab at baseline and at six weeks; intravitreal injection of 1.25 mg bevacizumab at baseline and sham injection at six weeks; and intravitreal injection of 1.25 mg bevacizumab at baseline and at six weeks with photocoagulation at three weeks.⁸ The results of the study demonstrated the benefits of bevacizumab in DME reduction, but further investigations are required to determine the optimal protocol.

Aflibercept (Eylea) is a fusion protein, ie, extracellular domains of human vascular endothelial growth factor receptors 1 (VEGFR1) and 2 (VEGFR2) fused to the constant region (Fc) of human IgG1 with potential antiangiogenic activity.⁹ The FDA, in November 2011, approved aflibercept for the treatment of wet AMD. The DA VINCI study compared aflibercept to focal/grid laser in patients with DME.¹⁰ Patients were assigned to five groups. Four of the groups used different aflibercept protocols, while the fifth used laser treatment alone.

Figure 1. Ultra-widefield fluorescein angiography of a patient with DME and areas of untreated midperipheral nonperfusion (arrows).

Mean BCVA and central retinal thickness were measured at baseline and every four weeks with the study endpoint at 24 weeks. Mean BCVA improved from +8.5 to +11.4 ETDRS letters in all aflibercept groups, compared with +2.5 letters in the laser group. Adverse ocular events in patients treated with aflibercept were generally consistent with those seen with other intravitreal anti-VEGF agents.

Steroids

The anti-inflammatory and antipermeability effects of corticosteroids are mediated by complex mechanisms. The most obvious pharmacological effects of corticosteroids are seen in blood vessel permeability. Since it became clear that chronic inflammation is also involved in pathogenesis of diabetic retinopathy, the role of corticosteroids in the treatment of DME has been investigated.

A randomized trial comparing intravitreal triamcinolone and focal/grid photocoagulation for DME showed that grid/focal laser was superior in improving mean BCVA (Snellen equivalent) when compared to 1 or 4 mg intravitreal free-preservative triamcinolone treatment, at two-year follow up (laser vs 1 mg triamcinolone, P = .02; laser vs 4 mg triamcinolone, P = .002).¹¹ High intraocular pressure (33% with 4 mg triamcinolone and 16% with 1 mg triamcinolone compared to 4% in the laser group) and cataract formation (51% with 4 mg and 23% with 1mg, compared to 13% in laser group) were the main ocular side effects observed in this clinical trial.

Despite the beneficial effect on visual acuity and macular edema, especially during the first months after initial treatment, intravitreal triamcinolone use is greatly limited by significant side effects, especially due to frequent retreatment need. Therefore, the need for an intravitreal sustained-release corticosteroid device that would be equally effective but safer was fully justified.

The Ozurdex dexamethasone intravitreal implant is a biodegradable device that has been approved by the FDA for macular edema secondary to central retinal vein occlusion and noninfectious uveitis. According to information provided by Ozurdex manufacturer Allergan at a meeting in Maribor, Slovenia, several studies have investigated Ozurdex for the treatment of DME.

It was proposed that dexamethasone intravitreal implantation in vitrectomized eyes might yield additional beneficial effects of BCVA improvement and CRT reduction than what would be expected for vitrectomy alone (the CHAMPLAIN study). The PLACID study compared the two groups (sham dexamethasone implant + laser photocoagulation vs dexamethasone implant + laser photocoagulation), but the results of that study have not yet been published.

The FAME study was a three-year, randomized, masked, controlled study in which patients were randomly divided into two groups: a group receiving a 0.59-mg Iluvien fluocinolone acetonide intravitreal implant and a group receiving laser alone.¹² BCVA improvement of three lines or more was found in 31.1% of the patients in the implanted group at three years. The main side effects observed were cataract formation and IOP elevation (61.4%); 33.8% required glaucoma surgery.

The above-mentioned studies show the potential of pharmacotherapy to be superior to laser treatment alone. Given the treatment options available to physicians, it is necessary to develop protocols based on scientific studies and clinical experience.

A SUGGESTED PROTOCOL

We would like to propose a protocol for the treatment of DME followed in our clinic, which is based on the clinical trials mentioned above and on our clinical experience as well.

The primary approach to treating DME is three monthly intravitreal anti-VEGF intravitreal injections (bevacizumab or ranibizumab). At monthly follow-ups, BCVA and CRT are checked. If BCVA has improved or CRT has decreased following three injections, we continue with anti-VEGF treatment until we observe further improvement in BCVA and CRT. If BCVA has not improved or has declined or CRT has not decreased after the three initial anti-VEGF injections, we proceed with Ozurdex. Follow-up examinations after implantation are conducted at 14 days and then monthly.

Our clinical experience in a limited number of cases suggests Ozurdex to be safe and effective treatment of DME. All of the patients have responded well. The positive effects of Ozurdex on BCVA and CRT are present for six months, usually with retreatment needed at four to five months after baseline. When considering retreatment, we can either suggest Ozurdex reimplantation or switching back to anti-VEGF, hoping that it might be more effective after CRT has already been reduced. We are currently investigating the best approach.

Why are anti-VEGF agents the drugs of choice in our protocol initially? Increased VEGF concentration is due to hypoxia present in the retina of patients with DME. Anti-VEGF drugs decrease vascular permeability and new vessel formation. We cannot entirely explain why some patients with DME do not respond well to anti-VEGF therapy alone. It is possible that other inflammatory agents (other than VEGF) play a dominant role in those patients.

Previous clinical studies showed the benefits of laser photocoagulation therapy.^4,11 Focal/grid laser is performed as initial therapy in our patients who are not able to come for frequent follow-ups due to financial issues, living abroad, etc. A fear of the side effects of intravitreal injections also contributes to the patients' decisions. Initial vitrectomy is advised in those patients presenting with macular traction.

CONCLUSION

Currently there are many treatment options available to physicians, and no one perfect approach exists. Therefore, further drug development and clinical investigations are required. The future will show whether combination therapy with existing agents or new agents will provide the best option for DME. RP

REFERENCES

1. Mavrikakis E. Macular edema in diabetes. Available at: http://emedicine.medscape.com/article/1224138-overview#a0104. Accessed April 11, 2012.
2. Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology. 2009; 116:73-79.
3. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-986.
4. National Eye Institute. Early Treatment Diabetic Retinopathy Study (ETDRS). Available at: http://www.nei.nih.gov/neitrials/static/study53.asp. Accessed April 11, 2012.
5. Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-1077.
6. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399-2405.
7. Mitchell P, Bandello F, Schmidt-Erfurth U, et al.; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-625.
8. Diabetic Retinopathy Clinical Research Network; Scott IU, Edwards AR, Beck RW, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Opthalmology. 2007;114:1860-1867.
9. National Cancer Institute. Definition of aflibercept. Available at: http://www.cancer.gov/drugdictionary?cdrid=38652. Accessed April 11, 2012.
10. Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011;118:1819-1826.
11. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1450.
12. Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011;118:1580-1587.