Retinopathy and macular oedema

Diabetic retinopathy is an ocular manifestation of systemic disease which affects up to 80% of all patients who have diabetes for 10 years or more. Research indicates that at least 90% of these new cases could be reduced if there were proper and vigilant treatment and monitoring of diabetic eyes. 

The case for screening diabetic eye disease has never been stronger now that newer therapies have come to the fore. The classification of diabetic retinopathy is broadly mild, moderate and severe non-proliferative but, as the disease progresses, severe non-proliferative diabetic retinopathy enters an advanced or proliferative stage when fragile blood vessels proliferate. 

Without timely treatment these new blood vessels can bleed and destroy the retina. Fibrovascular proliferation can also cause tractional retinal detachment. Diabetic retinopathy often has no early warning signs, which again underpins the importance of screening and early therapeutic intervention.

When to screen

Screening for retinopathy should be performed within three to five years after the onset of type 1 diabetes and shortly after the diagnosis of type 2 disease, with annual follow-up examinations in both types of diabetes.²

Modifiable risk factors for diabetic retinopathy include HbA1c levels, hypertension, cigarette smoking and dyslipidaemia. Tight control of blood glucose concentrations and blood pressure can reduce the risk for, and progression of, diabetic retinopathy. Dyslipidaemia in patients with diabetes is associated with progression of retinopathy and visual loss.

Diabetic macular oedema

Diabetic retinopathy is occasionally accompanied by macular oedema leading to a marked decline in visual acuity. Diabetic macular oedema (DME), with or without visual impairment, should be considered for treatment when it fulfils the Early Treatment Diabetic Retinopathy Study (ETDRS)¹ criteria for clinically significant oedema.

Several biochemical mechanisms have been implicated in the pathogenesis of DME. These mechanisms include protein kinase C-ß activation, increased vascular endothelial growth factor (VEGF) production, oxidative stress and accumulation of intracellular sorbitol and advanced glycosylation end products. 

Several factors contribute to the vascular disruption that characterises diabetic retinopathy/DME.³ The ETDRS has defined the standard for treatment of DME. The ETDRS defines clinically significant macular oedema (CSME) as follows:

• Retinal thickening present at, or within 500 microns of, the fovea
• Hard exudates if associated with macular thickening within 500 microns of the fovea
• Thickening greater than 1,500 microns within 1,500 microns of the fovea.

CSME can be confirmed demonstrating fluid leakage on fluorescein angiography or on optical coherence tomography. 

Diabetic macular oedema treatment

Prior to the advent of VEGF analogues, the standard treatment included the use of conventional focal or grid argon laser or the use of intravitreal corticosteroids in the form of triamcinalone acetonide. Now, with the use of anti-VEGF analogues supported by the latest evidence-based research, new options for the treatment of diabetic eye disease have evolved.

Ranibizumab (Lucentis), an intravitreal monoclonal antibody which acts as a VEGF inhibitor, was initially authorised for age-related macular degeneration. More recently it has been approved for the treatment of visual impairment due to macular oedema in diabetic patients. 

For DME with central involvement and associated vision loss, monthly ranibizumab monotherapy with treatment interruption and reinitiation based on visual acuity stability is recommended. These recommendations are based on randomised controlled trials of one to two years’ duration.

Ranibizumab is a monoclonal antibody fragment (Fab) derived from the same parent mouse antibody as bevacizumab (Avastin). It is much smaller than the parent molecule and has been affinity-matured to provide stronger binding to VEGF-A. Ranibizumab, which binds to and inhibits a number of subtypes of VEGF-A, may trigger the growth of new vessels, and leak blood and fluid into the eye. These leaky blood vessels may contribute to macular oedema as is found in DME. 

Researchers have demonstrated that ranibizumab, often in conjunction with laser treatment, results in better vision than laser treatment alone for DME. Laser treatment alone has been the gold standard of treatment care for the past 25 years. Approximately 50% of patients who received this new treatment experienced substantial visual improvement after one year, compared to 28% who received standard laser therapy. This study involved 52 clinical sites within the Diabetic Retinopathy Clinical Research Network (www.drcr.net), supported by the National Eye Institute. 

More recently, a randomised double-masked multicentre trial was performed to demonstrate superiority of ranibizumab (0.5mg) monotherapy or combined with laser over laser alone based on mean average change in best corrected visual acuity over 12 months in DME (RESTORE Study).⁴ There were 345 patients included in the study with type 1 or type 2 diabetes mellitus with associated DME. 

The RESTORE study demonstrated that ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. At one year, no difference was detected between the ranibizumab and ranibizumab/laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that seen in the treatment for age-related macular degeneration. Interestingly, the expanded two-year results reported are similar to results published previously and reinforce the conclusions of the one-year results of the RESTORE study. 

More importantly, based on RESTORE one-year follow-up data, ranibizumab monotherapy appears to be cost-effective relative to laser monotherapy.⁵

Cost-effectiveness of combination therapy is less certain and will require ongoing studies which will monitor disease progression and the need for additional ranibizumab therapy. 

In conclusion, ranibizumab is a safe therapy,⁶ and is both clinically and cost-effective. It has become the gold standard for patients with DME as first-line therapy, to prevent irreversible visual loss. 

References

1. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Ophthalmology 1987; 94: 761-774
2. Kristinson JK. Diabetic Retinopathy. Screening and prevention of blindness. A doctoral thesis. Acta Ophthalmol Scand Suppl 1997; (223): 1-76
3. Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology screening and novel therapies. Diabetes Care 2003; 26(9): 2653-2664
4. Mitchell P, Bandello F, Schmidt-Erfurth U et al. The RESTORE study. Ophthalmology 2011; 118(4): 615-625
5. Mitchell P, Annemans L, Gallagher M et al. Cost effectiveness of ranibizumab in treatment of diabetic macular oedema, causing visual impairment: evidence from the RESTORE trial. Br J Ophthalmol 2012; 96(5): 688-693
6. Massin P, Bandello F, Garweg JG et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study). Diabetes Care 2010; 33(11): 2399-2405