Dr Devinder Chauhan
MBBS FRCOphth MD FRANZCO
Vision Eye Institute, Melbourne VIC
Diabetic macular oedema (DME) is the main cause of vision loss in diabetes, affecting 27 per cent of type 1 diabetic patients within nine years of onset1 and up to 28 per cent of type 2 diabetic patients within 20 years of diagnosis.2 As the development of DME is insidious, many patients are asymptomatic until it involves the fovea; earlier detection is possible only through routine diabetic retinopathy screening and monitoring, ideally in a primary care setting.
Laser treatment for DME was first established as beneficial in 1981 and has remained the gold standard3 until recently. The primary goal of treatment of DME has historically been prevention of further vision loss. While the use of intravitreal agents is increasing, particularly with the recent PBS approval of ranibizumab for DME, focal laser treatment retains an important role, particularly in the treatment of DME, that may fit the definition of clinically significant macular oedema (CSME) but does not involve the foveal centre.
The Diabetic Retinopathy Clinical Research (DRCR) Network studies4,5,6 compared the use of intravitreal ranibizumab, an anti-VEGF autoantibody fragment used extensively to treat neovascular age-related macular degeneration (nvAMD), with both focal laser photocoagulation and intravitreal triamcinolone (corticosteroid).
The subjects in these studies had centre-involving DME with a foveal thickness of 250 microns or more and visual acuity of 6/9 or worse.
The studies also looked at the role of focal laser combined with intravitreal ranibizumab, either at the onset of treatment or as a ‘rescue’ therapy after six months of intravitreal injections if the DME was persistent. The ranibizumab was injected monthly and the steroids every three months for the first six months of the trial. The need for subsequent injections was determined using a combination of optical coherence tomography (OCT) and visual acuity criteria.
Figure 1. The OCT images with macular thickness maps and change analysis maps demonstrate the progression of diabetic macular oedema (DME) from August 2014 (A) to October 2014 (B). The vision at this stage was not affected but dropped to 6/12 in November 2014 (C), when monthly intravitreal anti-VEGF (initially a single bevacizumab and subsequently ranibizumab) were started. Image D demonstrates significant reduction in DME with a return visual acuity of 6/6.
The most significant findings of these studies relate to the visual acuity outcomes over the first two years in particular. It was shown that ranibizumab alone, with ‘rescue’ laser after six months had a better visual acuity outcome at two years than ranibizumab with laser at the onset, which, in turn, had a better outcome than triamcinolone alone. Nearly twice as many eyes had an improvement in vision of greater than 15 letters with ranibizumab than with laser.
The other findings of interest were that the visual acuity benefit of triamcinolone was equivalent to ranibizumab in eyes that were pseudophakic at the start of the trial and that the visual acuity benefit of laser alone increased by three years and was almost as good as in the ranibizumab arms of the study.
Finally, the most surprising finding of all was that there was reversal of retinopathy grade in many patients. That is, some patients had a reduction in grade of retinopathy, such as from severe non-proliferative retinopathy to mild-moderate non-proliferative. This was seen in about one quarter of all patients on ranibizumab and some patients with triamcinolone and laser; it was statistically significant only for ranibizumab in patients with severe non-proliferative retinopathy or worse.
Figure 2. Colour images of the same eye as in Figure 1 from in August 2014 (A) and July 2015 (B) demonstrate a significant reduction in intraretinal haemorrhages and an improvement in venous irregularity. There was an improvement in grading of the diabetic retinopathy from severe non-proliferative to moderate non-proliferative.
Unlike the lifelong need for ongoing intravitreal injections in nvAMD, the regimen of intravitreal ranibizumab injections consisted essentially of monthly injections for the first six months, with an average number of injections in the second six months between two and three. Subsequently, two to three injections were required in the second year and fewer in the third year of the extension study.
Many have adopted the DRCR protocol in the management of DME, but using pragmatic variants, often based on a ‘treat and extend’ regimen. As a result, many retinal specialists and their patients are seeing the benefits demonstrated in the DRCR studies. While the treatment burden of increasing numbers of patients treated is significant, this is only for a limited number of injections for most.
The use of intravitreal triamcinolone in pseudophakic eyes certainly reduces the treatment burden to the patient, doctor and society. With lower doses, such as 2 mg, rather than the standard 4 mg, similar results can be achieved with lower intraocular pressure raising complications.
Most Australian retinal specialists have used bevacizumab until relatively recently and would use aflibercept if it gains PBS approval. Both of these are also anti-VEGF agents and have been shown to be of little difference compared with ranibizumab in eyes with better visual acuity. However, in eyes with worse vision (~6/15 or worse) aflibercept is better than ranibizumab, which is better than bevacizumab.7
Critics of the high uptake of intravitreal therapy have mostly been concerned about the abandonment of laser in cases that are suitable; the cost to society of repeated injections in many patients where a similar visual result can be achieved with one or two laser treatments may be too high.
- Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology 1995; 102: 647-661.
- Klein R, Klein B E, Moss S E, Cruickshanks KJ. The Wisconsin Epidemiology Study of Diabetic Retinopathy. XV The longterm incidence of macular edema. Ophthalmology 1995; 102: 7-16.
- Indications for photocoagulation treatment of diabetic retinopathy. Diabetic Retinopathy Study Report no 14. The Diabetic Retinopathy Study Research Group. Int Ophthalmol Clin 1987; Winter 27: 239-253.
- Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008; 115: 1447-1449.
- Aiello LP, Edwards AR, Beck RW et al. Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2010; 117: 946-953.
- Beck RW, Edards AR, Aiello LP et al. Diabetic Retinopathy Clinical Research Network (DRCR.net). Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009; 127: 245-251.
- Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR et al. Comparative effectiveness randomized clinical trial of aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; 372: 1193-1203.