Diabetic eye disease, particularly diabetic retinopathy, remains one of the leading causes of preventable blindness among working-age adults worldwide. While early detection and glycemic control form the cornerstone of management, advanced disease often requires interventional therapy. In recent years, dual therapy strategies that combine intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents with other modalities such as laser photocoagulation or corticosteroids have demonstrated superior anatomic and functional outcomes compared to monotherapy in certain patient populations. Despite the accumulating evidence, these combination regimens have not been widely adopted across clinical settings. Understanding the specific barriers that impede uptake and implementing structured approaches to overcome them is essential for elevating the standard of care and preserving vision in patients with diabetic eye disease.

The Role of Dual Therapy in Managing Diabetic Retinopathy

Diabetic retinopathy progresses along a continuum from non-proliferative to proliferative stages, often accompanied by diabetic macular edema (DME). The pathophysiology involves complex interplay between VEGF-driven angiogenesis, inflammatory cytokine activation, and breakdown of the blood-retinal barrier. Monotherapies target individual pathways, but dual therapy aims to simultaneously address multiple disease mechanisms, potentially offering more robust and durable control.

Anti-VEGF Combined with Laser Photocoagulation

Combining anti-VEGF injections with focal or grid laser has been a well-studied approach, particularly for DME. The landmark Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I demonstrated that while ranibizumab monotherapy produced excellent visual outcomes, the addition of laser reduced the number of injections needed over time without compromising efficacy. Similarly, Protocol S showed that for proliferative diabetic retinopathy, ranibizumab alone was non-inferior to panretinal photocoagulation (PRP), but combination therapy may offer faster regression of neovascularization and less visual field loss. These findings support a role for dual therapy in reducing treatment burden while maintaining excellent visual outcomes.

Anti-VEGF Combined with Corticosteroids

Corticosteroid implants such as dexamethasone (Ozurdex) or fluocinolone acetonide (Iluvien) target inflammatory components of diabetic retinal disease. Combination with anti-VEGF agents has been evaluated in trials including the BEVORDEX study, which compared bevacizumab plus dexamethasone implant versus ranibizumab monotherapy for DME. Results indicated that combination therapy could achieve similar visual gains with fewer injections, particularly in eyes with a prominent inflammatory component. More recent work, such as the SCORE2 trial, has explored combination versus sequential therapy, highlighting the potential for synergistic effects when both angiogenic and inflammatory pathways are blocked early in the disease course. However, corticosteroid-related adverse events like cataract progression and intraocular pressure elevation require careful patient selection and monitoring.

Evidence from Pivotal Clinical Trials

Large randomized controlled trials have consistently supported the rationale for dual therapy. The RIDE and RISE trials established ranibizumab as effective for DME, and subgroup analyses showed that adjunctive laser reduced treatment frequency. The VIVID and VISTA trials for aflibercept similarly reported that combination with laser provided comparable visual outcomes with fewer injections over two years. Real-world data from registries like the IRIS® Registry also suggest that patients receiving combination therapy experience lower rates of treatment discontinuation and better long-term anatomic outcomes. These studies underscore that dual therapy is not merely an alternative but often a superior strategy for complex presentations such as refractory DME, eyes with substantial hard exudates, or those with pre-existing epiretinal membranes.

Barriers Hindering Adoption of Dual Therapy

Despite robust evidence, the translation of dual therapy from clinical trials to routine practice remains incomplete. Several interconnected barriers operate at the clinician, patient, and systemic levels.

Lack of Awareness and Limited Continuing Education

Many retina specialists and general ophthalmologists are not fully up-to-date with the latest clinical trial data supporting combination approaches. The volume of new evidence published annually is vast, and busy practitioners may rely on established monotherapy algorithms. Continuing medical education (CME) programs often focus on newer anti-VEGF agents rather than combination strategies. Furthermore, local opinion leaders and guideline committees may not emphasize dual therapy as a first-line option, reinforcing habitual practice patterns. Without deliberate efforts to disseminate trial results and practical decision-making algorithms, awareness gaps persist.

Cost and Reimbursement Challenges

The economic burden of intravitreal therapy is a significant concern. While anti-VEGF drugs themselves are expensive, adding a second modality such as a corticosteroid implant or laser procedure increases upfront costs. Reimbursement structures vary widely between healthcare systems and insurance plans. In the United States, Medicare and private payers may have separate reimbursement caps for injection and laser procedures, creating disincentives for same-session combination therapy. Prior authorization requirements for corticosteroid implants can cause delays, leading clinicians to choose monotherapy for simplicity. Additionally, for patients with high deductibles or copayments, the out-of-pocket expense of dual therapy may be prohibitive. This financial toxicity can discourage both physician recommendation and patient acceptance.

Inadequate Training and Experience

Performing laser photocoagulation in the era of anti-VEGF dominance requires skill and confidence. Many younger ophthalmologists trained in centers where lasers were used less frequently may lack hands-on experience with focal/grid laser for DME or PRP for proliferative disease. Similarly, inserting corticosteroid implants involves a slightly different technique and potential complications (e.g., implant migration, endophthalmitis risk). Without supervised training and proctored cases, clinicians may avoid combination therapy due to perceived procedural difficulty. Institutional protocols and simulation-based training could address this, but such resources are not universally available.

Patient Factors and Treatment Burden

Patients with diabetes often face a heavy treatment burden: multiple clinic visits, frequent injections, and monitoring for systemic and ocular side effects. Adding laser sessions (which may cause discomfort and temporary vision loss) or corticosteroid implants (with risk of cataract and glaucoma) can be perceived as increasing burden without guaranteed benefit. Patient education about the potential for fewer total injections over the long term and improved visual outcomes is critical, but time constraints during office visits limit thorough counseling. Health literacy, language barriers, and fear of medical interventions further complicate shared decision-making. Some patients may decline dual therapy simply because they feel overwhelmed by their existing regimen.

Strategies to Overcome Barriers

Addressing the multifaceted barriers to dual therapy adoption requires coordinated efforts across education, policy, guideline development, and patient engagement.

Enhancing Education and Training Programs

Structured CME courses focused on dual therapy should be developed and promoted by professional societies such as the American Academy of Ophthalmology and the European Society of Retina Specialists. These courses should include case-based learning, video demonstrations of combination techniques, and interactive discussions on patient selection. Hands-on workshops at annual meetings can improve procedural confidence. Additionally, online platforms offering on-demand modules with CME credit can reach clinicians who cannot travel. Training should also incorporate practical tips for managing corticosteroid-related side effects and dosing intervals. Incorporating dual therapy principles into residency and fellowship curricula will ensure that the next generation of ophthalmologists is comfortable with combination approaches from the start.

Advocating for Policy and Reimbursement Changes

Professional organizations should engage with payers to streamline prior authorization processes for corticosteroid implants and to remove disincentives for same-session combination procedures. Value-based payment models that reward long-term outcomes rather than per-procedure volume could encourage more rational use of dual therapy. Clinicians can also partner with hospital administrators to negotiate better drug pricing or participate in patient assistance programs that reduce out-of-pocket costs for eligible patients. Advocacy efforts should highlight the potential for dual therapy to reduce overall healthcare utilization by lowering injection frequency and preventing disease progression that requires more intensive interventions.

Updating Clinical Guidelines

Major clinical guidelines, including those from the American Academy of Ophthalmology Preferred Practice Patterns and the International Council of Ophthalmology, should explicitly include dual therapy as a recommended option for specific scenarios. When guidelines present combination therapy as a viable first-line or early second-line strategy, clinicians are more likely to adopt it. Guideline committees should regularly update their recommendations to reflect the latest evidence, and implementation tools such as quick-reference charts or decision support within electronic health records can help clinicians apply these guidelines at the point of care. For example, an alert that prompts consideration of a steroid implant when a patient has persistent DME after three anti-VEGF injections could standardize best practices.

Engaging Patients in Shared Decision-Making

Patient education materials in plain language, available in multiple languages, can explain the rationale for dual therapy, expected outcomes, and potential side effects. Decision aids that compare monotherapy versus combination therapy using visual analog scales or simplified outcome data can empower patients to participate actively. During clinic visits, allocating dedicated time for counseling—perhaps through a trained nurse educator or health coach—can address individual concerns. Follow-up phone calls or telemedicine check-ins after initiating dual therapy can improve adherence and early detection of adverse events. When patients understand that one additional laser session or implant may lead to fewer injections over the next two years, many become more willing to try combination approaches.

Practical Implementation in Clinical Practice

For clinicians ready to incorporate dual therapy, a stepwise approach can minimize disruption and maximize benefits.

Timing and Sequencing of Therapies

The optimal timing of adding a second modality depends on the clinical scenario. For DME, a common strategy is to start with monthly anti-VEGF monotherapy and consider adding focal/grid laser or a corticosteroid implant if there is suboptimal response after four to six injections. For proliferative diabetic retinopathy, combining anti-VEGF with PRP can be done at the time of initial presentation, especially if there is high-risk disease or vitreous hemorrhage. Some experts advocate for early combination in eyes with DME and substantial hard exudates, as corticosteroids may hasten exudate resolution. The DRCR.net Protocol U evaluated adding intravitreal dexamethasone after three ranibizumab injections in DME non-responders, showing benefit in the combination arm. Using a standardized algorithm and documenting the rationale for combination therapy can aid in consistency and future treatment planning.

Monitoring and Follow-Up

After initiating dual therapy, follow-up intervals should be tailored. Patients receiving a corticosteroid implant need intraocular pressure checks within 30 days and then periodically; those receiving laser require evaluation for laser-related complications such as subretinal fibrosis or visual field loss. Optical coherence tomography remains essential for tracking anatomic response. The decision to taper or stop one component of dual therapy after disease quiescence is individualized. Some clinicians continue maintenance anti-VEGF injections at extended intervals while others reduce injection frequency if the implant provides sustained control. Clear communication between the physician and the patient about the expected course and potential side effects is vital for long-term success.

Future Directions and Research Needs

Future research should focus on refining patient selection criteria for dual therapy, perhaps using biomarkers such as inflammatory cytokine levels or genetic polymorphisms. Randomized trials comparing different dual therapy regimens (e.g., aflibercept plus laser vs. ranibizumab plus dexamethasone) head-to-head would provide practical guidance. Additionally, studies examining cost-effectiveness from a societal perspective can strengthen the case for policy changes. Real-world evidence from large registries will continue to inform optimal sequencing and duration of combination therapy. The development of longer-acting drug delivery systems, such as sustained-release anti-VEGF implants, may eventually reduce the need for combination therapy, but for the foreseeable future, dual therapy remains an important tool in the retina specialist’s armamentarium.

Conclusion

Dual therapy that combines anti-VEGF agents with laser photocoagulation or corticosteroids has proven efficacy in controlling diabetic retinopathy and diabetic macular edema, often with fewer total treatments than monotherapy alone. Yet widespread adoption is hindered by gaps in clinician education, financial barriers, training deficits, and patient concerns. By implementing targeted educational initiatives, advocating for favorable reimbursement policies, updating clinical guidelines, and empowering patients through shared decision-making, the retina community can overcome these obstacles. Overcoming these barriers is not just about following guidelines—it is about delivering the best possible care to a growing population of patients with diabetes, preserving their vision and quality of life for years to come. For further guidance, clinicians should refer to the AAO Preferred Practice Pattern for Diabetic Retinopathy and review the latest evidence from National Eye Institute resources. Ongoing research and clinical collaboration will ensure that dual therapy becomes a standard, accessible option for all appropriate patients.