Rethinking NPDR: From a Single Pathway to Three Distinct Phenotypes

As vitreoretinal surgeons, we recognize that not all patients with nonproliferative diabetic retinopathy (NPDR) progress to vision-threatening complications. A groundbreaking review by Cunha-Vaz et al. (2025) reframes our understanding of NPDR progression by identifying three distinct disease phenotypes, each with different risks for developing clinically significant macular edema (CSMO) or proliferative diabetic retinopathy (PDR). This paradigm shift, enabled by modern non-invasive imaging, offers a more personalized approach to risk stratification and management.

🔍 The Three Phenotypes of Early Diabetic Retinal Disease

The authors propose that NPDR progression follows three primary pathways, which may occur alone or in combination:

1. Phenotype A: Neurodegeneration-Dominant

   • Hallmark: Progressive thinning of the ganglion cell layer + inner plexiform layer (GCL+IPL).

   • Imaging: OCT.

   • Progression: Slow. Eyes with this phenotype (approx. 50% of mild NPDR) showed no progression to CSMO or PDR in a 5-year study.

2. Phenotype B: Blood-Retinal Barrier (BRB) Breakdown-Dominant

   • Hallmark: Subclinical macular edema, increased vascular permeability.

   • Imaging: OCT for retinal thickness.

   • Progression: Intermediate risk. Combined with Phenotype A, these groups represent ~75% of mild NPDR with a low risk of vision-threatening complications.

3. Phenotype C: Ischemia-Dominant

   • Hallmark: Progressive capillary non-perfusion (hypoperfusion).

   • Imaging: OCT Angiography (OCTA) is key, showing decreased skeletonized vessel density (SVD) and perfusion density (PD).

   • Progression: High Risk. This is the only phenotype strongly associated with progression to CSMO and PDR.

Key Takeaway: Identifying the ischemic phenotype (C) is critical, as it signals the patient is on a high-risk trajectory.

📈 The Ischemic Phenotype: A Two-Stage Model

For high-risk Phenotype C eyes, progression follows a sequence:

1. Hypoperfusion Stage:

   • Characterized by progressive capillary closure.

   • Measured by decreasing SVD/PD on OCTA.

   • Closure begins in the superficial capillary plexus (SCP), then involves the deep capillary plexus (DCP), starting centrally and extending peripherally.

2. Hyperperfusion Stage:

   • A compensatory, dysregulated response to ischemia.

   • Characterized by the development of intraretinal microvascular abnormalities (IRMAs) and dilated shunt vessels.

   • Surrogate Marker: A rapid increase in microaneurysm (MA) count and turnover on color fundus photography (CFP).

   • This inflammatory, pro-angiogenic environment sets the stage for CSMO and PDR.

Clinical Implication: Monitoring the balance between hypoperfusion (OCTA metrics) and hyperperfusion (MA turnover) allows dynamic risk assessment.

🛠️ Practical Implications for the Vitreoretinal Surgeon

1. Incorporate OCTA into Routine Assessment: For patients with moderate NPDR (ETDRS 43+) or those progressing rapidly, OCTA is no longer just a research tool. It is essential for identifying the ischemic phenotype by quantifying capillary dropout.

2. Risk Stratify by Phenotype, Not Just ETDRS Level: A patient with moderate NPDR (ETDRS 43) and significant capillary non-perfusion on OCTA (Phenotype C) is at far greater risk than a patient with the same ETDRS level but a neurodegeneration-dominant profile (Phenotype A).

3. Monitor Progression with Combined Imaging:

   • OCTA tracks the hypoperfusion stage (SVD/PD decline).

   • CFP tracks the hyperperfusion response (rising MA turnover).

   • Together, they signal acceleration toward vision-threatening complications.

4. Tailor Management and Follow-up: Patients identified as Phenotype C warrant more frequent monitoring and earlier consideration of systemic or local interventions to halt ischemic progression.