WHAT IS PROLIFERATIVE DIABETIC RETINOPATHY?

Pathophysiology

Diabetic retinopathy (DR) is the second-most common microvascular complication of diabetes mellitus after diabetic neuropathy, and a leading cause of preventable blindness in working-age adults worldwide.1 Chronic hyperglycaemia (high blood sugar) damages the delicate microvasculature of the eye, which leads to the physical and functional failure of retinal capillaries. This leads to retinal ischaemia, which in turn triggers upregulation of vascular endothelial growth factor (VEGF) via hypoxia-inducible factor (HIF) signalling pathways.3

VEGF drives abnormal proliferation of new blood vessels arising from the disc (neovascularisation of the disc, NVD), peripheral retina (neovascularisation elsewhere, NVE) or on the iris (NVI) and angle (NVA). Vitreous VEGF levels in eyes with PDR are markedly elevated compared with controls, and directly correlate with the activity of neovascularisation (Figure 1).4 These new vessels are structurally deficient, lacking pericyte support, and have a propensity to bleed, which results in vitreous haemorrhage, while fibrovascular membrane contraction can lead to tractional retinal detachment – both of which may cause sudden and severe visual loss.5 Neovascularisation in the angle can lead to secondary angle closure and synechial apposition, which causes neovascular glaucoma. Without treatment, 30–40% of patients with high-risk PDR are at risk of severe visual loss within two years.6

Figure 1. Proliferative diabetic retinopathy with localised tractional retinal detachment and breakthrough vitreous haemorrhage despite panretinal photocoagulation (image provided by author).

Risk Factors

The prevalence of PDR is strongly determined by duration of diabetes and degree of glycaemic control. Approximately 50% of patients with type 1 diabetes develop DR after 10 years, rising to >90% after 20 years; PDR is present in a substantial subset of these patients.7 Among patients with type 2 diabetes, 10–20% will have some degree of DR at the time of diagnosis, which reflects the insidious onset of the disease and delays in diagnosis.7

The following risk factors are independently associated with the development and progression of DR:

Duration of diabetes: The single strongest predictor of retinopathy development; risk increases with each decade of disease.7

Poor glycaemic control: The UK Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT) demonstrated that intensive blood sugar control significantly reduces retinopathy incidence and progression.8,9

Hypertension: The UKPDS also demonstrated that tight blood pressure control reduced retinopathy progression by 34%.10

Pregnancy: Pregnancy accelerates DR progression, particularly in women with pre-existing retinopathy, and requires increased monitoring during the antenatal and postnatal periods.11

Obstructive sleep apnoea (OSA): OSA is linked to an increased rate of DR progression to vision-threatening complications and need for ophthalmic intervention.12

Optometrists should elicit this risk factor profile at each visit in diabetic patients. Patients with multiple risk factors should have increased surveillance frequency and a low threshold for referral regardless of current retinopathy grade, as per the Royal Australian and New Zealand College of Ophthalmology’s (RANZCO) Screening and Referral Pathway for Diabetic Retinopathy.13

RANIBIZUMAB FOR PDR: PBS-LISTING MECHANISM, AND CLINICAL EVIDENCE

The PBS Listing: What Optometrists Need to Know

Ranibizumab (Lucentis, Novartis) received a PBS listing for the treatment of PDR in Australia in 2025 – the first government-subsidised anti-VEGF therapy specifically approved for this indication.2 Prior to this listing patients with PDR, but no diabetic macular oedema (DMO) managed with intravitreal anti-VEGF agents, facing the full private cost of the drug (between AU$1,000–$2,000) in addition to the surgeon’s injecting fees – a prohibitive expense that limited access for most patients. PBS subsidy substantially reduces this burden, enabling eligible patients to access treatment at the standard PBS co-payment rate ($25 for general patients, and $7.70 for concession card holders). This improves equity of access, particularly for patients in regional and lower socioeconomic settings.

The eligibility criteria for PBS-subsidised ranibizumab for PDR is straightforward: treatment must be initiated and supervised by an ophthalmologist, and the diagnosis of PDR must be confirmed by clinical examination and retinal imaging. Refer to the PBS schedule for the full criteria. Optometrists play a key role in identifying eligible patients and facilitating timely referral to ophthalmologists to ensure that patients can access treatment.

Figure 2. Optos autofluorescence image of a patient who underwent panretinal photocoagulation and focal laser in the early 2000s, demonstrating scar expansion over time (image provided by author).

Figure 3. Protocol S, five-year follow-up: Mean change from baseline in the combined total score from the 30-2 pattern. Light blue=PRP arm, dark blue = ranibizumab with rescue PRP, orange = ranibizumab without rescue PRP.19

Mechanism of Action of Ranibizumab

Ranibizumab is a humanised monoclonal antibody fragment that binds to VEGF-A, preventing it from interacting with VEGF receptors.14 It blocks angiogenesis (growth of new, abnormal blood vessels) and reduces vascular leakage, the latter of which is useful for treating macular oedema associated with diabetes and retinal vein occlusions. Ranibizumab suppresses the key downstream signalling cascades responsible for endothelial proliferation and migration.14 In the context of PDR, this results in regression of neovascular fronds (NVD, NVE, NVI, or NVA), reduction of neovascular leakage, and – with sustained treatment – stabilisation or resolution of fibrovascular proliferation.15

Following intravitreal injection, ranibizumab distributes rapidly to the retina within 6–24 hours. The elimination half-life in human vitreous is approximately nine days, with therapeutic concentrations (>0.1 µg/ml) maintained for about 29 days.16 Systemic absorption is low – serum concentrations are 90,000 times lower than vitreous concentrations due to rapid systemic metabolism and excretion, which underpins its favourable systemic safety profile to other VEGF inhibitors.16

Clinical Evidence Supporting Ranibizumab in PDR

Panretinal photocoagulation (PRP) has been the cornerstone of PDR management since the Diabetic Retinopathy Study (1976) demonstrated a greater than 50% decrease in risk of severe vision loss in patients with high-risk proliferative diabetic retinopathy.6 PRP’s primary strength is durability and cost-effectiveness, which makes it particularly well suited to patients where long-term injection compliance is uncertain. However, PRP is destructive and irreversible in nature.

Evidence shows that after PRP, 60% of patients reported worsened dark adaptation, 38% reported difficulty with night driving, and 19% failed driving field criteria.17 A Japanese study also showed that 90% of PRP scars increase with time, with higher annual expansion rates at the posterior pole compared to the mid-peripheral retina.18 PRP can also trigger worsening DMO, which can further affect fitness to drive and result in the need for rescue intravitreal anti-VEGF therapy. Central and peripheral visual field loss can be economically catastrophic for patients who need to meet commercial driving standards or need to drive at night for work (e.g. shift workers).

There is a growing body of evidence that has demonstrated the role of ranibizumab, and anti-VEGF in general, for the treatment of PDR. The Diabetic Retinopathy Clinical Research Network (DRCR.Net) Protocol S trial established in 2015 the clinical non-inferiority of ranibizumab to PRP for PDR.5 At two years, mean visual acuity change was +2.8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the ranibizumab group versus +0.2 letters in the PRP group. Ranibizumab-treated eyes also demonstrated significantly lower rates of vitrectomy (4% versus 15%), significantly better peripheral visual field preservation, and significant lower rates of developing DMO compared with the PRP group.5 Protocol S also demonstrated that 50% of patients in the PRP arm required rescue intravitreal injections for persistent neovascularisation or DMO at some point during the initial two years of the study. The five-year follow-up of Protocol S patients showed that patients who were initially treated solely with intravitreal ranibizumab versus PRP had better visual field preservation (-201dB change in total point score versus -527dB)19 (Figure 3).19

The CLARITY trial, published in The Lancet in 2017, demonstrated that intravitreal aflibercept – another anti-VEGF agent – was superior to PRP for best-corrected visual acuity (BCVA) at 52 weeks (+3.9 versus +0.9 ETDRS letters), providing corroborating evidence for the class efficacy of anti-VEGF agents in PDR.20 A recently-published meta-analysis of 19 studies in Ophthalmology Retina (2025) concluded that anti-VEGF and combination treatments could be regarded as an alternative approach to PRP alone, with improved BCVA and increased likelihood of complete regression of total neovascularisation at 12 months.21

However, when patients with PDR undergoing anti-VEGF injections are lost to follow-up, their visual and anatomic outcomes are inferior to those who received PRP.22 The decision to choose anti-VEGF over PRP must be made with careful consideration of patient-related factors, not the least of which is the clinician’s assessment of likely compliance, patient location, and other comorbidities that might affect ongoing clinic attendance. Anti-VEGF treatment alone should only be considered for patients with reliable follow-up, and in cases where there is significant material benefit to avoiding laser (e.g. preserving peripheral vision and night vision in commercial drivers and truck drivers).

Table 1. RANZCO Screening and Referral Pathway for Diabetic Retinopathy (2022). DR Severity Classification and Optometrist Referral Framework (excluding diabetic maculopathy).13

Anti-VEGF therapy should also be considered in patients with PRP in the setting of refractory disease, e.g.

• Failure of regression of neovascularisation,

• Increasing neovascularisation of the retina or iris,

• New vitreous haemorrhage, or

• New areas of neovascularisation.

In cases of involutional PDR, vitreous haemorrhage may occur due to vitreous traction on involuted neovascularisation. In these eyes further treatment may not be required, especially in the absence of venous dilation, a biomarker for increased VEGF activity.

Taken together, the evidence base supports ranibizumab as an effective, vision-preserving treatment for PDR that offers particular advantages over laser in eyes with concurrent DMO, poor peripheral visual field, occupational requirements for peripheral and night vision, and high-risk features where surgical rates can be reduced.5,20

DIAGNOSING PDR AND WHEN TO REFER

Classification of Diabetic Retinopathy

The classification established by the ETDRS remains the international standard for grading DR severity.23 The stages of DR progress from no DR through to mild, moderate, and severe non-proliferative DR (NPDR) to PDR. High-risk PDR is defined as NVD greater than quarter of the disc area, NVD with any pre-retinal or vitreous haemorrhage, or NVE greater than half the disc area with vitreous haemorrhage.6 Eyes with high-risk PDR are at the greatest risk of severe visual loss and require more urgent intervention.

In clinical practice, the simplified International Clinical Diabetic Retinopathy Disease Severity Scale is widely used by optometrists and provides a clinically applicable framework aligned with the ETDRS.24 This is incorporated into the RANZCO Screening and Referral Pathway for Diabetic Retinopathy, which also includes a framework for the timing of ophthalmology referrals13 (Table 1).

Examination Approach for PDR Detection

Dilated fundus examination with slit lamp biomicroscopy remains the practical gold standard for diabetic retinopathy screening.24 However, mydriatic fundus photography, including seven-field ETDRS photography or ultra-widefield (UWF) retinal imaging, provides superior documentation of diabetic retinopathy and is increasingly available in Australian optometric practices. The ease and advantage of imaging a single-capture UWF image over standard seven-field protocols, which require multiple retinal photographs, is evident. UWF has been shown to detect more lesions – including peripheral NVE – than standard fundus photography.25 Optical coherence tomography (OCT) of the macula is also essential to detect co-existing DMO, which can be present without visible oedema on fundoscopy, and can have significant implications for visual acuity outcomes and treatment planning.26 OCT angiography (OCT-A), where available, also provides information previously available only through invasive fluorescein angiography (Figure 4) such as:27

Figure 4. Comparison of red-free photographs and OCT-A in diabetic retinopathy (image courtesy of the Centre for Eye Health).28

• Visualisation of the superficial and deep capillary plexuses,

• Identification of neovascularisation, and

• Assessment of the foveal avascular zone.

When to Refer: Practical Guidance

Optometrists should refer any patient with suspected or confirmed PDR to an ophthalmologist with a special interest in medical retina or vitreoretinal surgery. Referral urgency is guided by clinical findings, as outlined in Table 1. The RANZCO Screening and Referral Pathway for Diabetic Retinopathy provides a nationally endorsed framework that defines referral urgency by DR grade and can be used as a reference standard for referral decision making.13

When completing a referral, optometrists should provide the receiving ophthalmologist with the following information to facilitate efficient triage and treatment planning:

• Current BCVA,

• DR grade and any change from prior assessments,

• Retinal imaging (fundus photographs, OCT, OCT-A, if available),

• Current diabetes medications and recent HbA1c, if known, and

• Relevant medical history including renal disease, cardiovascular history and anticoagulation use, if known.

COLLABORATIVE CARE OF PDR

The Shared-Care Model

Management of DR in the Australian health system is best understood within a shared-care model. The ophthalmologist is responsible for treatment decisions including laser and intravitreal injection administration, while the optometrist plays a pivotal role in screening, monitoring between treatment cycles, and systemic risk factor reinforcement.13 This model improves capacity within the ophthalmology sector, reduces patient inconvenience, and leverages optometrists’ existing relationships with diabetic patients in the community. Effective shared care requires clear, bidirectional communication between the optometrist and the treating ophthalmologist, including timely reporting of any clinical findings that may indicate disease reactivation or complications. General practitioners and endocrinologists similarly play a key role in maintaining glycaemic control and improving metabolic health, to reduce the risk of other diabetic complications such as nephropathy, peripheral vascular disease, heart attacks, and strokes.

Particularly in rural and remote areas, optometrists may be asked to contribute to monitoring diabetic patients via fundus photography and OCT. Key parameters to assess and document at monitoring visits include: visual acuity; neovascularisation status; OCT central subfield thickness (as a surrogate for DMO activity); and intraocular pressure. Any change from prior baseline should be communicated to the treating ophthalmologist promptly with supporting imaging, regardless of whether a scheduled injection appointment is imminent.

Red Flags During Treatment

Optometrists who monitor PDR patients between treatment visits must be alert to clinical signs that may indicate disease reactivation, treatment failure, or injection-related complications. The following red flags require prompt contact with, or re-referral to, the treating ophthalmologist:

New or recurrent vitreous haemorrhage. Sudden new floaters or visual obscuration in a patient with PDR should prompt same-day contact with the treating ophthalmologist, as vitreous haemorrhage may indicate reactivation of neovascularisation, or tractional membrane development.

Sudden visual acuity loss of two or more lines. Unexplained acuity loss may indicate vitreous haemorrhage, tractional retinal detachment, or worsening macular oedema.

Raised intraocular pressure. Increased IOP may be a sign of NVA leading to neovascular glaucoma. Gonioscopy should be urgently performed to look for angle vessels, and even if they are not seen, the patient should be urgently referred back to their treating ophthalmologist for review.

Iris neovascularisation. New vessels on the iris surface represent an advanced stage of ischaemia-driven neovascularisation and carry a high risk of neovascular glaucoma. This requires same-day ophthalmology referral.

Reactivation of neovascularisation on imaging. Any new NVD or NVE, or growth of previously documented lesions, noted on fundoscopy, retinal photography or OCT-Abetween planned visits should be reported to the treating ophthalmologist, as this may indicate the need for interval reduction, treatment change, or rescue PRP.

Ocular pain or marked conjunctival injection post-injection. Endophthalmitis following intravitreal injection has an estimated incidence of approximately one in 3,000 injections and requires emergency ophthalmic assessment and treatment.29 Classic features include pain, visual loss, conjunctival hyperaemia, and anterior chamber cells or hypopyon appearing 24–72 hours post-injection.30 If endophthalmitis is suspected, the patient should be referred immediately to their treating ophthalmologist or a tertiary hospital with access to immediate ophthalmology emergency services for prompt treatment.

PATIENT EDUCATION

Optometrists are exceptionally well placed to deliver ongoing education to their patients with diabetes by view of the regular and often long-standing contact they have with them. Evidence consistently demonstrates that patient health literacy and understanding of their condition is associated with better treatment adherence, more timely presentation for care, and improved long-term outcomes.31

The following core concepts should form the basis for patient education conversations with individuals with diabetes who are at risk of, or have been diagnosed with, PDR:

The natural history of PDR. Patients should understand that DR and PDR develop silently – they may have no symptoms until significant damage has already occurred. The absence of visual symptoms does not mean that the eye is healthy, and regular monitoring is therefore non-negotiable, even when vision feels normal.1

The link between systemic control and DR progression. The DCCT demonstrated that intensive glycaemic control reduced the risk of retinopathy progression by 76% in type 1 diabetics, and the UKPDS demonstrated a 21% reduction in DR progression with tight blood pressure control.8,10 These figures are compelling and should be communicated in accessible language to patients.

What intravitreal injections involve. Many patients are anxious at the prospect of intraocular injections. Clear, calm explanation of the procedure – which is performed under topical or subconjunctival anaesthesia and is typically well tolerated – along with realistic discussion of treatment duration, helps to reduce avoidance and improve treatment retention.32 It is especially helpful if the optometrist has had firsthand experience of intravitreal injections as a clinic observer.

The importance of treatment adherence. Unlike PRP, which is typically a finite treatment, intravitreal anti-VEGF therapy requires multiple injections over a number of years in some instances. Patients must understand that missing injections or delaying treatment can lead to rapid reactivation of neovascularisation, and risk developing a vitreous haemorrhage or tractional detachment.

Driving and functional implications. Patients should be advised that visual acuity, visual field, and contrast sensitivity may all be affected by PDR and its treatment. Optometrists should counsel patients on their legal obligations regarding driving fitness and consider formal visual field assessment when field loss is suspected following PRP or as a result of PDR-related damage.

Recognising warning symptoms. Every patient with PDR should be counselled to present within 24 hours to their optometrist or ophthalmologist if they notice any sudden onset of new floaters, flashers, a curtain or shadow across their vision, sudden visual loss, or any acute change in visual quality. These symptoms may herald vitreous haemorrhage or tractional detachment.

Supporting Indigenous Patients

The burden of diabetes and diabetic eye disease is disproportionately carried by Aboriginal and Torres Strait Islander Australians, who have rates of DR and PDR significantly higher than the non-Indigenous population.33 Optometrists practising in communities with high Indigenous populations should be familiar with culturally safe communication approaches, should offer access to Aboriginal health workers or interpreters where available, and should be aware of the culturally specific barriers to eye care engagement.33

CONCLUSION

PDR remains one of the most serious and visually consequential complications of diabetes, but it is also one of the most preventable causes of blindness when detected and treated in a timely fashion.1 The PBS listing of ranibizumab for PDR represents a transformative development in retinal practice – making effective, vision-preserving anti-VEGF therapy accessible to a population of patients for whom this mode of therapy was previously cost-prohibitive in the absence of DMO.2

Intravitreal ranibizumab is a viable option for the treatment of PDR, however its pharmacological – rather than ablative – mechanism means that sustained treatment adherence is non-negotiable, and the optometrist’s role in maintaining patient engagement between ophthalmology visits is as critical as any examination skill. By embracing their role as primary screener, shared-care monitors, and patient educators, optometrists can meaningfully reduce the vision loss attributable to PDR in the community.

This article is sponsored by Novartis Pharmaceuticals.

References available at mieducation.com.