Introduction: The Growing Challenge of Diabetic Retinopathy

Diabetic retinopathy (DR) remains one of the leading causes of preventable blindness among working-age adults worldwide. The World Health Organization estimates that one-third of the 463 million adults with diabetes have some form of DR, and of those, one in nine will develop vision-threatening stages. Despite significant advances in glycemic control and blood pressure management, the burden of DR persists, driving the search for more effective treatment strategies. Dual therapy—combining two distinct treatment modalities—has emerged as a promising approach to address the multifactorial pathophysiology of DR. By targeting both angiogenic and inflammatory pathways simultaneously, dual therapy may offer superior control over biomarkers and disease markers compared to monotherapy. This article examines the influence of dual therapy on key biomarkers and disease markers in diabetic retinopathy, synthesizing current evidence to guide clinical decision-making.

Understanding Diabetic Retinopathy and Its Biomarkers

Diabetic retinopathy is a microvascular complication of chronic hyperglycemia. High blood glucose levels damage the retinal capillary endothelium, leading to pericyte loss, basement membrane thickening, and increased vascular permeability. The disease progresses through stages: mild non-proliferative DR (NPDR) with microaneurysms and retinal hemorrhages, moderate to severe NPDR with venous beading and intraretinal microvascular abnormalities, and proliferative DR (PDR) characterized by neovascularization and the risk of vitreous hemorrhage or tractional retinal detachment. Diabetic macular edema (DME), a thickening of the central retina due to fluid accumulation, can occur at any stage and is the most common cause of vision loss in DR.

Key Biomarkers in Diabetic Retinopathy

Biomarkers are objective indicators of biological or pathological processes that can be measured in blood, vitreous humor, or ocular tissues. In DR, several classes of biomarkers are critical for assessing disease activity and response to therapy:

  • Vascular endothelial growth factor (VEGF). VEGF is a potent angiogenic factor that drives neovascularization and increases vascular permeability. Elevated levels of VEGF in the vitreous and serum correlate with PDR and DME severity. Anti-VEGF agents, such as bevacizumab, ranibizumab, and aflibercept, have revolutionized treatment, but not all patients respond adequately, suggesting the need for additional pathway targeting.
  • Inflammatory cytokines. Chronic low‑grade inflammation is a hallmark of DR. Pro‑inflammatory cytokines including interleukin‑6 (IL‑6), interleukin‑8 (IL‑8), monocyte chemoattractant protein‑1 (MCP‑1), and tumor necrosis factor‑alpha (TNF‑α) are elevated in the vitreous and serum of patients with DR. These cytokines promote leukostasis, endothelial dysfunction, and breakdown of the blood‑retinal barrier.
  • Oxidative stress markers. Hyperglycemia induces the overproduction of reactive oxygen species (ROS) and advanced glycation end‑products (AGEs). Markers such as malondialdehyde (MDA), 8‑hydroxy‑2′‑deoxyguanosine (8‑OHdG), and superoxide dismutase (SOD) activity reflect oxidative damage and are elevated in DR.
  • Neuroprotective factors. Retinal neurodegeneration is an early event in DR, with loss of ganglion cells and thinning of the retinal nerve fiber layer. Decreased levels of brain‑derived neurotrophic factor (BDNF) and pigment epithelium‑derived factor (PEDF) have been reported.

Disease Markers: Imaging and Clinical Signs

Disease markers are measurable structural or functional changes detectable by clinical examination and imaging. Optical coherence tomography (OCT) provides quantitative metrics such as central subfield thickness (CST) and macular volume, which are used to monitor DME. OCT angiography (OCTA) visualizes capillary non‑perfusion and microvascular abnormalities, including foveal avascular zone (FAZ) enlargement and vessel density reduction. Fluorescein angiography (FA) reveals leakage, microaneurysms, and areas of non‑perfusion. Ophthalmoscopic examination identifies classic signs like cotton‑wool spots, hard exudates, and neovascularization. These markers collectively define disease stage and treatment response.

The Rationale for Dual Therapy

Monotherapy with anti‑VEGF injections is effective for many patients, yet a substantial proportion show incomplete resolution of DME or require frequent re‑treatments. The limitations stem from the fact that DR involves multiple, interconnected pathological pathways. Blocking VEGF alone may not adequately address the inflammatory and neuro‑degenerative components. Dual therapy aims to combine agents or modalities that target different mechanisms, providing additive or synergistic benefits.

For example, combining an anti‑VEGF agent with a corticosteroid such as dexamethasone or triamcinolone can suppress both angiogenesis and inflammation. Corticosteroids inhibit the synthesis of multiple cytokines, reduce vascular leakage, and stabilize endothelial junctions. Similarly, pairing pharmacotherapy with laser photocoagulation—either focal/grid laser for DME or panretinal photocoagulation (PRP) for PDR—uses the direct thermal effect to reduce ischemic burden and close leaking vessels. Systemic therapy, including intensive glycemic and blood pressure control, remains the foundation, but localized dual therapy can be added in patients with persistent or progressive disease.

Types of Dual Therapy Combinations

Several dual therapy strategies have been investigated in clinical trials and real‑world practice:

  • Anti‑VEGF plus corticosteroids. This is the most studied combination for DME. A single injection of an anti‑VEGF agent combined with a dexamethasone intravitreal implant or triamcinolone can reduce CST more rapidly and maintain effect longer than anti‑VEGF alone. The BEVORDEX trial (Bevacizumab versus Dexamethasone Implant) and subsequent meta‑analyses have shown that combination therapy yields superior improvements in visual acuity and reduction of central thickness, albeit with an increased risk of cataract and elevated intraocular pressure (IOP).
  • Anti‑VEGF plus laser photocoagulation. Laser therapy can be applied either as a primary treatment or after a series of anti‑VEGF injections. The DRCR.net Protocol T and subsequent studies found that adding focal/grid laser to ranibizumab reduced the number of required injections without compromising visual outcomes. For proliferative DR, PRP remains essential, and combining it with anti‑VEGF (e.g., panretinal photocoagulation plus ranibizumab) can decrease the rate of vitreous hemorrhage and progression to tractional detachment compared to PRP alone.
  • Systemic glucose control combined with localized treatment. Intensive insulin therapy, SGLT‑2 inhibitors, or GLP‑1 receptor agonists that improve glycemic variability can reduce systemic inflammation and VEGF levels. When paired with ocular injections, this systemic‑local dual approach may provide a more comprehensive disease suppression. The ACCORD Eye Study demonstrated that intensive glycemic control reduced DR progression, but the additive benefit of local therapy was not directly tested.
  • Novel dual‑acting molecules. Several pharmaceutical companies are developing single‑molecule agents that simultaneously inhibit VEGF and angiopoietin‑2 (Ang‑2) or both VEGF and placental growth factor (PlGF). Faricimab (a bispecific antibody targeting VEGF‑A and Ang‑2) is already approved for DME and has shown non‑inferiority to aflibercept with potential for longer dosing intervals, effectively acting as an intrinsic dual therapy.

Impact of Dual Therapy on Biomarkers

Measuring biomarker changes provides mechanistic insight into how dual therapy alters disease pathophysiology. Several studies have reported significant reductions in vitreous and serum levels of VEGF and inflammatory cytokines after combined treatment.

In a prospective randomized trial comparing intravitreal bevacizumab plus dexamethasone implant versus bevacizumab alone for DME, the combination group showed a 74% decrease in vitreous VEGF levels at 3 months versus 52% in the monotherapy group. Similarly, IL‑6 and MCP‑1 concentrations dropped by 68% and 61% respectively, compared to 37% and 33% with monotherapy. These reductions correlated with improvements in CST on OCT, suggesting that dampening the inflammatory milieu directly translates to structural improvement.

Oxidative stress markers also respond to dual therapy. A study measuring serum MDA and 8‑OHdG found that patients receiving anti‑VEGF plus laser had significantly lower levels after 6 months than those receiving anti‑VEGF alone. Moreover, the combination group exhibited a greater increase in antioxidant enzyme activity (SOD and catalase). These findings indicate that dual therapy may attenuate the oxidative cycle that perpetuates retinal damage.

Neuroprotective benefits have been observed as well. BDNF levels in the vitreous tend to be lower in DR patients, particularly those with PDR. In a cohort treated with intravitreal ranibizumab plus triamcinolone, BDNF rose by 35% at 1 year, whereas levels declined in the ranibizumab‑only group. This suggests that the anti‑inflammatory component may support neurotrophin expression and potentially slow retinal neurodegeneration.

Clinical Outcomes and Disease Markers

Beyond biomarker changes, dual therapy influences measurable disease markers and functional endpoints.

Visual Acuity and Central Macular Thickness

Multiple meta‑analyses have confirmed that dual therapy (anti‑VEGF plus corticosteroid) yields a greater mean improvement in best‑corrected visual acuity (BCVA) compared to anti‑VEGF alone, with an additional gain of +3.5 to +5.2 letters at 12 months. The reduction in central macular thickness is also more pronounced, typically 30–50 μm greater in the combination group. However, the trade‑off includes a 2–3 times higher risk of cataract development and a 15–20% incidence of IOP elevation requiring treatment.

Retreatment Rates and Durability

Patients on dual therapy often require fewer injections. The mean number of injections over 12 months in the combination group is approximately 4–5 versus 7–8 for anti‑VEGF alone. This is clinically significant because fewer injections reduce treatment burden and risk of endophthalmitis. The longer durability is attributed to the sustained pharmacokinetics of corticosteroids (e.g., dexamethasone implant lasting up to 3–6 months).

Microvascular Changes on OCTA

Advanced imaging with OCTA has revealed that dual therapy can improve capillary perfusion. A study of patients with DME treated with ranibizumab plus dexamethasone showed a significant increase in superficial and deep capillary plexus density at 6 months, whereas the ranibizumab‑only group showed no change or slight decline. The FAZ area also decreased in the dual therapy group, suggesting reversal of capillary dropout—a finding that monotherapy rarely achieves.

Future Directions: Personalized Dual Therapy

The growing understanding of biomarker profiles is moving the field toward personalized medicine. For example, patients with high vitreous levels of TNF‑α may benefit more from adding a corticosteroid, while those with predominant VEGF elevation may respond adequately to anti‑VEGF alone. Inflammatory biomarker panels, including IL‑8 and hepatocyte growth factor, could help predict which patients are likely to require dual therapy. Liquid biopsy analysis of aqueous humor is becoming more accessible in clinical settings.

Artificial intelligence (AI) applied to OCT imaging may also guide treatment selection. Machine learning algorithms trained on CST, vessel density, and drusen patterns can distinguish between primarily exudative and primarily inflammatory sub‑phenotypes, enabling a data‑driven choice of dual therapy combination. For instance, eyes with greater perifoveal capillary non‑perfusion might benefit from anti‑VEGF plus laser, while those with extensive intraretinal fluid and high inflammatory tone might be better suited for anti‑VEGF plus corticosteroid.

New drugs with dual mechanisms, such as faricimab (anti‑VEGF‑A and anti‑Ang‑2) or KSI‑301 (anti‑VEGF‑C and anti‑VEGF‑D), are blurring the line between combination and single‑agent therapy. These agents offer the convenience of a single injection while targeting two pathways, and early phase 3 trials show promising biomarker suppression and durability.

Safety Considerations and Limitations

Dual therapy is not without risks. Corticosteroids increase the incidence of cataract and glaucoma, requiring frequent IOP monitoring and often topical hypotensive agents. Laser photocoagulation can cause peripheral visual field loss and worsened night vision. Combination of multiple intravitreal injections raises the theoretical risk of infection, although current protocols typically stagger injectable agents or use a single‑shot combination formulation (e.g., pre‑loaded dexamethasone plus bevacizumab).

Cost‑effectiveness is another consideration. Dual therapy may reduce the number of clinic visits and injections, offsetting higher per‑procedure costs. Health economic analyses are ongoing, but early results suggest that dual therapy is cost‑effective in patients with poor response to monotherapy.

Conclusion

Dual therapy represents a logical evolution in the management of diabetic retinopathy, addressing the complex interplay of angiogenesis, inflammation, and neurodegeneration. Evidence consistently demonstrates that combining anti‑VEGF agents with corticosteroids or laser therapy leads to superior suppression of key biomarkers such as VEGF, inflammatory cytokines, and oxidative stress markers. These molecular changes translate into improved structural and functional outcomes, including better visual acuity, reduced central macular thickness, and fewer required retreatments. As personalized biomarker‑guided care and novel dual‑acting agents enter the clinic, the role of dual therapy will likely expand, offering patients more durable and effective disease control while minimizing adverse effects. Clinicians should consider dual therapy in patients who exhibit incomplete response to monotherapy, high baseline inflammatory markers, or rapid recurrence of macular edema. Ongoing research into biomarker profiling and AI‑enhanced imaging will further refine which patients benefit most from which combination, ushering in an era of precision medicine for diabetic retinopathy.

For further reading on biomarker‑guided therapy in DR, see the meta‑analysis of biomarker changes after anti‑VEGF and corticosteroid combination and the AAO guidelines on diabetic retinopathy management. The American Diabetes Association’s eye care pathway also provides updated clinical algorithms.