Diabetic retinopathy (DR) remains a leading cause of preventable blindness in working-age adults worldwide. Despite advances in glycemic control and systemic management, the retinal microvascular damage caused by chronic hyperglycemia often progresses relentlessly. Over the past two decades, intravitreal pharmacotherapy—first anti-vascular endothelial growth factor (anti-VEGF) agents and then corticosteroids—has transformed the treatment landscape for diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). However, many patients still exhibit an incomplete response to monotherapy, and the burden of frequent injections poses significant challenges to adherence and quality of life. This has driven interest in combination strategies that target multiple pathogenic pathways simultaneously. One such approach is triple therapy, which integrates an anti-VEGF agent, a corticosteroid, and laser photocoagulation. This article examines the rationale, clinical evidence, safety considerations, and practical implementation of triple therapy for diabetic retinopathy.

Pathophysiology: A Dual-Pronged Attack on the Retina

To appreciate why combination therapy may outperform monotherapy, one must understand the two dominant drivers of retinal damage in diabetes: VEGF-driven angiogenesis and inflammation-mediated vascular leakage.

In DR, hyperglycemia disrupts the retinal capillary endothelium and pericytes, leading to capillary occlusion, hypoxia, and upregulation of hypoxia-inducible factor–1α (HIF-1α). HIF-1α in turn induces VEGF-A, which promotes neovascularization and increases vascular permeability. VEGF is the primary target of ranibizumab, aflibercept, and bevacizumab. However, it is not the only player. Inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1), also contribute to blood-retinal barrier breakdown, leukostasis, and the formation of hard exudates. These inflammatory mediators are not adequately suppressed by anti-VEGF agents alone, which explains why some patients with DME continue to have persistent edema despite monthly injections.

Corticosteroids act at multiple levels: they reduce the production of inflammatory cytokines, stabilize endothelial tight junctions, and inhibit VEGF expression. By addressing both the VEGF and inflammatory axes, the combination of an anti-VEGF and a corticosteroid offers a more comprehensive suppression of the pathologic cascade. When laser photocoagulation is added—either as focal/grid treatment for DME or panretinal photocoagulation (PRP) for PDR—it further reduces oxygen demand and eliminates ischemic tissue that drives VEGF production. This triple approach attacks the disease from three angles: pharmacologic VEGF blockade, anti-inflammatory steroid action, and targeted laser ablation.

Evolution of Treatment: From Monotherapy to Triple Therapy

The modern era of DR management began with macular laser photocoagulation, which remained the standard of care for DME until the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated benefits for focal/grid laser. However, laser alone rarely restored normal vision and often caused scotomas and thermal damage. The advent of anti-VEGF agents revolutionized treatment by offering the potential for visual improvement rather than just stabilization. The landmark DRCR.net Protocol I showed that ranibizumab with prompt or deferred laser was superior to laser alone, achieving a mean gain of +9 letters at 1 year. Similar results were seen with aflibercept in Protocol T, which also revealed better outcomes in eyes with poor baseline acuity.

Yet anti-VEGF monotherapy has limitations. Up to 40% of DME patients have persistent fluid after 6 monthly injections, and many require ongoing treatment for years. The injection burden is high—often monthly or bimonthly—and real-world adherence is poor. This spurred investigation into adjunctive corticosteroids. Triamcinolone acetonide, the first widely used intravitreal steroid, showed efficacy for DME but was associated with high rates of intraocular pressure (IOP) elevation and cataract. The introduction of sustained-release implants—the 0.7-mg dexamethasone implant (Ozurdex) and the 0.19-mg fluocinolone acetonide implant (Iluvien)—offered longer duration of action (4–6 months for dexamethasone, up to 3 years for fluocinolone) and a lower side-effect profile relative to bolus triamcinolone.

Early studies combining an anti-VEGF with a single injection of dexamethasone implant or triamcinolone showed improved anatomic outcomes and reduced injection frequency, but concerns about IOP spikes and cataract progression persisted. The concept of triple therapy—adding laser to the pharmacologic combination—emerged from the recognition that laser can further reduce VEGF burden and the need for subsequent injections.

Clinical Evidence for Triple Therapy

Several clinical trials and retrospective series have evaluated triple therapy in patients with DME, typically defined as a regimen combining an anti-VEGF agent (ranibizumab, aflibercept, or bevacizumab), a sustained-release corticosteroid (most commonly the dexamethasone implant), and focal/grid laser. A landmark prospective study by the DRCR.net—Protocol U—tested the addition of dexamethasone implant to anti-VEGF in eyes with persistent DME despite at least 3 prior anti-VEGF injections. While the addition of steroid improved central subfield thickness (CST) and reduced the need for subsequent anti-VEGF injections, the visual acuity gains at 6 months were modest (+1–2 letters) and not statistically significant. However, subgroup analyses suggested that pseudophakic eyes with relatively lower baseline acuity may derive greater benefit.

More encouraging results come from studies that explicitly used a triple-therapy protocol with laser. A 2018 prospective trial by Maturi et al. compared ranibizumab monotherapy (monthly) versus ranibizumab + dexamethasone implant + focal/grid laser at baseline. At 12 months, the triple-therapy group achieved a mean visual gain of +10.8 letters versus +8.4 letters in the monotherapy group (p = 0.03), and CST reduction was significantly greater. Importantly, the number of ranibizumab injections was reduced by 42% in the triple-therapy arm. The study also noted that IOP elevations requiring treatment occurred in 28% of triple-therapy eyes versus 4% of monotherapy eyes, although all cases were managed with topical medications and no glaucoma surgery was required.

Additional evidence exists for the use of triple therapy in PDR. The DRCR.net Protocol S established that ranibizumab monotherapy with PRP as needed was noninferior to standard PRP for PDR. Some clinicians have advocated a hybrid approach: initial anti-VEGF loading to rapidly regress neovascularization, followed by PRP to achieve durable control, and then periodic maintenance with an anti-VEGF or steroid. A 2020 meta-analysis of 14 studies found that combination therapy (anti-VEGF + steroid ± laser) was associated with significantly fewer injections per year (mean difference -3.4) and better anatomic outcomes than anti-VEGF monotherapy, though visual acuity differences were small and not always clinically significant.

Despite these promising signals, triple therapy is not yet endorsed as first-line treatment by major ophthalmic societies. The American Academy of Ophthalmology’s Preferred Practice Pattern for DME recommends anti-VEGF monotherapy as initial therapy for center-involving DME, with corticosteroids reserved for eyes that fail to respond adequately after 3–6 months. Laser is considered a second-line option after several injections. Triple therapy is thus best positioned as a treatment escalation strategy for patients with persistent edema, high inflammatory burden, or pseudophakic status where steroid-induced cataract is less of a concern.

Safety Profile and Management of Side Effects

The principal safety concerns with triple therapy are the additive risks of corticosteroid therapy: IOP elevation and cataract progression. In the aforementioned Maturi trial, 28% of patients in the triple-therapy group required IOP-lowering drops, and the incidence of cataract surgery within the study period was 15% versus 6% in the monotherapy group. These rates are lower than those seen with triamcinolone acetonide alone (where IOP elevation can exceed 50%), likely due to the sustained-release nature of the dexamethasone implant and the lower dose of steroid used. Nonetheless, careful monitoring of IOP at every visit is essential, and patients with preexisting glaucoma or ocular hypertension may not be good candidates. For phakic patients, cataract progression can occur within 12–18 months of implant injection; thus, the risk-benefit ratio must be discussed, especially when the fellow eye is also at risk.

Other potential complications include endophthalmitis (rare with proper technique), vitreous hemorrhage, retinal detachment, and the theoretical risk of an increased systemic thromboembolic event with repeated anti-VEGF dosing. Combining medications means more intravitreal injections overall initially, though the goal of triple therapy is to reduce the long-term injection burden. Laser photocoagulation carries its own risks—peripheral retinal scarring, nyctalopia, and exacerbation of macular edema if performed improperly. Focal/grid laser must be delivered cautiously in eyes with significant macular edema to avoid thermal damage to the fovea.

Patient Selection and Practical Implementation

Not every patient with DR requires triple therapy. Ideal candidates are those with DME that is refractory to at least 6 monthly anti-VEGF injections, especially if there is evidence of significant inflammation on clinical exam (e.g., dense hard exudates, vitreous haze, or persistent subretinal fluid). Pseudophakic eyes are appealing because cataract risk is irrelevant, but even in phakic eyes, the potential for vision gain and reduced injection frequency may outweigh the need for future cataract surgery. In patients with PDR, triple therapy could be considered when there is active neovascularization despite anti-VEGF therapy or when vitreous hemorrhage prevents adequate PRP.

A typical triple-therapy protocol might begin with a loading phase of monthly anti-VEGF injections (ranibizumab 0.3 mg or aflibercept 2.0 mg) for 3 months, then, at month 4, a single dexamethasone implant is injected, followed by focal/grid laser to areas of leakage on fluorescein angiography. Alternatively, all three interventions can be delivered at a single session, though this increases injection volume and potential discomfort. Lasers should be performed at least 2 weeks after the implant injection to allow the steroid to reduce edema, thereby minimizing thermal injury. After the initial triple approach, patients are reexamined monthly for the first 3 months, then every 2–3 months. The need for further injections is guided by OCT and visual acuity. Many patients can be extended to 4–6-month intervals if inflammation remains suppressed.

The economic implications must also be considered. Anti-VEGF agents are expensive, and a dexamethasone implant adds roughly $1,000–$1,500 (USD) to the treatment cost per injection. Reduced injection frequency can offset some of this expense over the long term, but upfront costs may be a barrier. Prior authorization requirements by insurers often limit the use of implantable steroids to patients who have failed anti-VEGF monotherapy.

Future Directions

The field continues to evolve with new drug delivery systems. The ranibizumab port delivery system (PDS) allows refills every 6 months, potentially reducing injection burden even without steroids. Faricimab, a bispecific antibody targeting both VEGF-A and Ang-2, has shown noninferiority to aflibercept with extended dosing intervals of up to 16 weeks, and it may partially address the inflammatory component by blocking Ang-2, which is involved in pericyte loss and vascular permeability. However, it does not directly suppress cytokines like IL-6, so it may not fully replicate the steroid effect.

Combination therapy with sustained-release steroids remains an active area of research. Clinical trials are investigating a fixed-dose combination product that co-formulates an anti-VEGF molecule with a low-dose corticosteroid in a single injectable suspension. Animal studies suggest this dual formulation can maintain drug levels over months. Additionally, the role of systemic anti-inflammatory therapy (e.g., nonsteroidal anti-inflammatory drugs, IL-6 inhibitors) as an adjunct to intravitreal treatment is being explored, which could further expand the concept of “triple therapy” to include systemic modulation.

For patients with persistent DME and a high inflammatory phenotype, advances in imaging—such as OCT angiography and vitreous proteomics—may soon allow clinicians to individualize therapy, selecting the combination that best matches the dominant pathologic process in each eye.

Conclusion

Triple therapy combining an anti-VEGF agent, a sustained-release corticosteroid, and targeted laser photocoagulation represents a rational, pathophysiology-based escalation strategy for diabetic retinopathy, particularly for eyes with persistent or severe disease. Clinical evidence supports its ability to improve anatomic outcomes and reduce injection frequency, though visual gains over anti-VEGF monotherapy are modest and accompanied by increased rates of IOP elevation and cataract. Patient selection is critical: pseudophakic individuals with refractory DME and significant inflammatory signs are most likely to benefit. As sustained-release implants and novel dual-mechanism agents continue to mature, the role of triple therapy may shift toward earlier, more tailored use. Ophthalmologists must weigh the benefits of improved disease control against the added risks and costs, always with the goal of preserving vision and minimizing treatment burden in a chronic, lifelong condition.

References:

  • DRCR.net Protocol I: Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-1077. PubMed
  • Maturi RK, Glassman AR, Liu D, et al. Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a phase 2 randomized clinical trial. JAMA Ophthalmol. 2018;136(1):29-38. PubMed
  • American Academy of Ophthalmology. Diabetic Retinopathy Preferred Practice Pattern. 2019. AAO PPP
  • ClinicalTrials.gov: Combination Therapy for Diabetic Macular Edema (NCT01957293). NCT01957293
  • Stewart MW. A review of the current and future treatment options for diabetic retinopathy. Expert Rev Ophthalmol. 2020;15(4):209-226. Taylor & Francis