Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus, leading to visual impairment if left untreated. This review discusses the use of optical coherence tomography angiography (OCTA) as a diagnostic tool for the early detection and management of DR. OCTA is a fast, non-invasive, non-contact test that enables the detailed visualisation of the macular microvasculature in different plexuses. OCTA offers several advantages over fundus fluorescein angiography (FFA), notably offering quantitative data. OCTA is not without limitations, including the requirement for careful interpretation of artefacts and the limited region of interest that can be captured currently. We explore how OCTA has been instrumental in detecting early microvascular changes that precede clinical signs of DR. We also discuss the application of OCTA in the diagnosis and management of various stages of DR, including non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), diabetic macular oedema (DMO), diabetic macular ischaemia (DMI), and pre-diabetes. Finally, we discuss the future role of OCTA and how it may be used to enhance the clinical outcomes of DR.

BACKGROUND: Retinal ischaemia is present to a greater or lesser extent in all eyes with diabetic retinopathy (DR). Nonetheless, our understanding of its pathogenic mechanisms, risk factors, as well as other characteristics of retinal ischaemia in DR is very limited. To date, there is no treatment to revascularise ischaemic retina.
METHODS: Review of the literature highlighting the current knowledge on the topic of retinal ischaemia in DR, important observations made, and underlying gaps for which research is needed.
RESULTS: A very scarce number of clinical studies, mostly cross-sectional, have evaluated specifically retinal ischaemia in DR. Interindividual variability on its natural course and consequences, including the development of its major complications, namely diabetic macular ischaemia and proliferative diabetic retinopathy, have not been investigated. The in situ, surrounding, and distance effect of retinal ischaemia on retinal function and structure and its change over time remains also to be elucidated. Treatments to prevent the development of retinal ischaemia and, importantly, to achieve retinal reperfusion once capillary drop out has ensued, are very much needed and remain to be developed.
CONCLUSIONS: Research into retinal ischaemia in diabetes should be a priority to save sight.

BACKGROUND: Diabetic macular ischaemia (DMI) is a complication of diabetic retinopathy that leads to irreversible vision loss. DMI is characterised by reduced retinal vessel density and enlargement of the foveal avascular zone (FAZ). Despite its clinical burden, there is no formal consensus on the definition of DMI, and no approved treatment. Semaphorin 3A (Sema3A) is an axonal guidance molecule that blocks revascularisation of the ischaemic retina. Sema3A modulation is therefore a promising mechanism of action for the treatment of ischaemic eye diseases. BI 764524 is an intravitreal anti-Sema3A ischaemia modulator agent.
METHODS: HORNBILL (NCT04424290) is a phase I/IIa trial comprising a non-randomised, open-label, single rising dose (SRD) part and a randomised, masked, sham-controlled multiple dose (MD) part to investigate the safety, tolerability and early biological response of ischaemia modulator BI 764524 in adults (≥18 years) with DMI. DMI will be defined using optical coherence tomography angiography (OCTA) as either any degree of disruption in the retinal vascularity (SRD) or a FAZ of ≥0.5 mm2 (MD). Subjects in the SRD part will receive 0.5, 1.0 or 2.5 mg of BI 764524; the maximum tolerated dose will then be used in the MD part. A minimum of 12 subjects will be enrolled into the SRD part; planned enrollment is 30 for the MD part. The primary endpoint of the SRD part is the number of subjects with dose-limiting adverse events (AEs) until day 8. The primary endpoint of the MD part is the number of subjects with drug-related AEs from baseline to end of study, and secondary endpoints include change from baseline in the size of the FAZ, best-corrected visual acuity and central retinal thickness.
CONCLUSIONS: DMI is a poorly defined condition with no treatment options. HORNBILL is the first clinical trial to assess a treatment for DMI and to use OCTA as a means to define and examine DMI. The OCTA data generated in this trial could form the basis of formal diagnostic criteria for DMI. Furthermore, the novel mechanism of action (Sema3A modulation) explored in this trial has the potential to revolutionise the treatment landscape for patients with DMI.
BACKGROUND: ClinicalTrials.gov NCT04424290 ; EudraCT 2019-004432-28. Registered on 9 June 2020.

Diabetic macular ischaemia (DMI) is traditionally defined and graded based on the angiographic evidence of an enlarged and irregular foveal avascular zone. However, these anatomical changes are not surrogate markers for visual impairment. We postulate that there are vascular phenotypes of DMI based on the relative perfusion deficits of various retinal capillary plexuses and choriocapillaris. This review highlights several mechanistic pathways, including the role of hypoxia and the complex relation between neurons, glia, and microvasculature. The current animal models are reviewed, with shortcomings noted. Therefore, utilising the advancing technology of optical coherence tomography angiography (OCTA) to identify the reversible DMI phenotypes may be the key to successful therapeutic interventions for DMI. However, there is a need to standardise the nomenclature of OCTA perfusion status. Visual acuity is not an ideal endpoint for DMI clinical trials. New trial endpoints that represent disease progression need to be developed before irreversible vision loss in patients with DMI. Natural history studies are required to determine the course of each vascular and neuronal parameter to define the DMI phenotypes. These DMI phenotypes may also partly explain the development and recurrence of diabetic macular oedema. It is also currently unclear where and how DMI fits into the diabetic retinopathy severity scales, further highlighting the need to better define the progression of diabetic retinopathy and DMI based on both multimodal imaging and visual function. Finally, we discuss a complete set of proposed therapeutic pathways for DMI, including cell-based therapies that may provide restorative potential.

OBJECTIVE: Diabetic macular ischaemia (DMI) is an important cause of visual loss in patients with diabetes, but its relationship to the larger retinal vessels is unknown. We examined whether retinal vessel calibre is related to DMI.
METHODS: Clinic-based case-control study of patients with type 2 diabetes. The presence and severity of DMI was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) protocols from fundus fluorescein angiographic (FFA) images. Custom software was used to quantify the greatest linear dimension and area of the foveal avascular zone (FAZ). Retinal vessel calibre was measured using a semi-automated software on fundus fluorescein images.
RESULTS: Of 53 patients examined, 18 (34%), 18 (34%) and 17 (32%) had no/mild, moderate and severe DMI, respectively. Persons with moderate or severe DMI had narrower mean retinal arteriolar calibre than persons with no/mild DMI (140.6 μm 95% confidence interval (CI) 134.7, 146.4 versus 150.7 μm, 95% CI 142.5, 158, p = 0.04). The association remained after multivariate adjustment for age, gender, previous panretinal photocoagulation, neovascularization at the disc and elsewhere and diabetic retinopathy severity. Increased FAZ size was also associated with narrower arteriolar calibre. Retinal venular calibre and arteriole to venule ratio (AVR) were not associated with DMI.
CONCLUSIONS: Retinal arteriolar narrowing was associated with moderate-to-severe macular ischaemia in eyes with diabetic retinopathy. This suggests that larger vessels other than capillaries may also be associated with DMI.