Addressing the Burden of Vision Loss From Diabetic Eye Disease

Friedenwald lecturer outlines past accomplishments and anticipated advances. Cheryl Guttman Krader reports

Lloyd P Aiello MD, PhD, was honoured as the Friedenwald Awardee at the virtual ARVO 2021 meeting for his work that has transformed the treatment of diabetic eye disease. His lecture provided a historical overview of developments that have changed the global paradigm for the evaluation, management, and treatment of diabetic retinopathy (DR) and diabetic macular oedema (DME) and offered a glimpse into what he believes will be an exciting future.

In beginning and ending his talk, Dr Aiello emphasised the advances he described could not have been realised without the participation of a host of researchers around the world.

“To me, this award is not so much a recognition of the work that our laboratory has been fortunate to be a part of, but rather a testament to the incredible efforts of so many exceptionally talented individuals worldwide to reduce the visual loss and alleviate the suffering associated with diabetes,” said Dr Aiello, Professor of Ophthalmology and Director of the Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

THE BEGINNING OF THE ANTI-VEGF ERA In the mid-1960s, work by Dr Aiello’s father, Lloyd M Aiello MD, and grandfather, William P Beetham MD, introducing panretinal photocoagulation (PRP) for the treatment of proliferative DR (PDR) was the first paradigm shift in the management of diabetic eye disease. However, the discovery of VEGF led to an even more transformative change. Research by Dr Lloyd P Aiello and colleagues providing evidence that VEGF in the vitreous of eyes with PDR was directly responsible for retinal endothelial cell growth, and animal studies from his group and others showing that VEGF inhibition could block hyperoxia-induced retinal neovascularisation was a major step in DR research.

The ability to bring anti-VEGF therapy into the clinical arena was greatly facilitated by work of the DR Clinical Research Network (now known as the DRCR Retina Network), of which Dr Aiello was the founding chair. DRCR.net Protocol I was the first large scale randomised clinical trial to evaluate the effect of VEGF inhibition on vision loss from DME, and its findings together with those of other studies initiated the paradigm shift for the treatment of centre-involved DME with reduced vision.

Subsequent studies sought to expand the role of anti-VEGF therapy by investigating its use for treating PDR and nonproliferative DR (NPDR). DRCR.net Protocol S showed noninferiority of intravitreal ranibizumab compared to PRP for improving VA after two and five years in eyes with PDR. It also demonstrated that anti-VEGF therapy had some advantages. Two-year results from DRCR.net Protocol W showed that compared to sham, aflibercept treatment in eyes with moderate to severe NPDR reduced the rates of PDR or centre involvedDME development. Preventive treatment with aflibercept did not confer a VA benefit compared with treatment initiated after the development of PDR or CME.

“Thus, with regards to NPDR, there are factors favouring use of anti-VEGF and those favouring monitoring,” Dr Aiello said.

EXPANDING FOCUS While research investigating treatments for diabetic eye disease is continuing, the therapeutic advances are supporting interest in strategies for optimising outcomes.

“A major hurdle for DR therapy is lack of patient awareness because it is a major contributing factor for nonadherence to eye care guidelines and poor visual outcomes,” said Dr Aiello. He discussed findings from a recent study that showed the extent of this problem.

The limitations associated with use of ETDRS 7-field photography to evaluate retinopathy severity are being overcome with the availability of ultrawide field (UWF) cameras. Dr Aiello described research looking for prognostic markers identified from UWF retinal imaging and investigating UWF angiography.

“Overall, the retina periphery appears to hold substantial, possibly unique, information that may permit better assessment of retinopathy progression risk. Furthermore, evolving technologies, such as artificial intelligence, peripheral OCT, UWF fluorescein angiography, and others may yield additional predictive value if they are used to assess the retinal periphery,” Dr Aiello said.

“If such findings are confirmed, current standard DR severity grading approaches may require modification to include these parameters for optimal risk assessment. Indeed, the Diabetic Retinal Disease Staging Project of the Restoring Vision Moonshot is already underway.”

The goal of the latter project is to provide an updated diabetic retinal staging system, to incorporate relevant advances, and provide prognostic information necessary to better address early disease, disease progression, development and use of therapeutic interventions, and treatment effectiveness.

UPCOMING RESEARCH Dr Aiello ended his talk with a brief description of some ongoing DRCR.net protocols. In addition to Protocol AA and W, these include AE, investigating photobiomodulation for DME; AC, comparing initial aflibercept vs bevacizumab with aflibercept as needed for centre involved-DME and VA 20/50 or worse; and AF, evaluating effects of fenofibrate on contrast sensitivity, OCT angiography, visual field, and DR severity.

Further into the future, studies are expected investigating recently discovered protective factors and non-VEGFA dependent pathological pathways. Meanwhile artificial intelligence and deep learning approaches for detecting diabetic eye disease are being increasingly pursued and some are already FDA-approved.

“A major hurdle for DR therapy is lack of patient awareness because it is a major contributing factor for nonadherence to eye care guidelines and poor visual outcomes,”