Management of patients with diabetic retinopathy depends on the severity of the retinopathy and whether DME is present.8 Patients with mild, moderate, or severe NPDR have a 15.6%, 44.6%, and 62.6% chance of developing DME, respectively.54 Owing to the risk of developing complications, follow-up examinations are recommended every 6 to 12 months for those with mild to moderate NPDR and every 2 to 4 months for patients with severe NPDR and non-high-risk proliferative diabetic retinopathy.8

Standard treatment of diabetic retinopathy is anti-VEGF injections, which are used as off-label or US Food and Drug Administration–approved treatment for all stages of diabetic retinopathy.8,55

NPDR. The American Academy of Ophthalmology Preferred Practice Pattern regarding patients with diabetic retinopathy and no DME recommends considering anti-VEGF only in patients with severe NPDR.8 However, recent studies have shown benefit in patients with milder disease. PANORAMA (Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Non-proliferative Diabetic Retinopathy)56 and the Diabetic Retinopathy Clinical Research Retina Network Protocol W57 looked at patients with moderate to severe NPDR and moderately severe to severe NPDR, respectively, both without DME. In these studies, patients treated with anti-VEGF injections had similar vision acuity outcomes compared with sham but a reduced risk of progression to proliferative diabetic retinopathy and development of center-involved DME.

Of US retina specialists treating very severe NPDR without DME, 60% closely monitor the condition and encourage systemic glycemic control, 25% consider anti-VEGF therapy in some patients with poor glycemic control, around 8% consider it in all or most patients, and 3% consider it in some patients with good glucose control and compliance.58,59 Additionally, among those treating patients with severe NPDR without clinically significant DME, 52% do not recommend anti-VEGF therapy; 39.1% said they would recommend it if extensive peripheral nonperfusion was present on fluorescein angiography, and 27.5% would recommend it if fellow eye pathology were present.60

Proliferative diabetic retinopathy. Clinical trials have evaluated visual acuity outcomes in patients with proliferative diabetic retinopathy treated with ranibizumab vs panretinal photocoagulation. Gross et al61 showed that anti-VEGF treatment is noninferior to photocoagulation in patients with and without DME, and Sivaprasad et al62 showed that anti-VEGF treatment is superior in patients without DME. However, physicians should assess patient adherence, as patients with proliferative diabetic retinopathy treated with panretinal photocoagulation who were lost to follow-up longer than 6 months had better anatomic and functional outcomes compared with those treated with anti-VEGF therapy.63

Most ophthalmologists treat patients with high-risk proliferative diabetic retinopathy and center-involved DME with both anti-VEGF therapy and laser. In a survey of US retina specialists, 69.9% of respondents said that they would start anti-VEGF therapy and plan for concurrent or future panretinal photocoagulation; 26% said they would treat with anti-VEGF injections and later assess the need for panretinal photocoagulation.59

DME. First-line therapy for patients with DME is intravitreal anti-VEGF injections.8 The RISE and RIDE (Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus) trials showed that ranibizumab significantly improved vision in patients with DME and reduced diabetic retinopathy severity across all stages.64 Anti-VEGF treatment is initiated with monthly injections for 3 to 6 months.65 The Diabetic Retinopathy Clinical Research Retina Network Protocol V evaluated patients with center-involved DME and visual acuity of 20/25 or better. It found that these patients should be observed with follow-up every 2 to 4 months, as initial treatment with either aflibercept or laser did not result in significant vision improvements compared with observation.66

Owing to insurance and costs, most patients are first treated with bevacizumab and, after treatment failure is demonstrated, are switched to another anti-VEGF therapy.67 However, in the Diabetic Retinopathy Clinical Research Retina Network Protocol T trial comparing the efficacy of intravitreal aflibercept, bevacizumab, and ranibizumab in center-involved DME, patients with a visual acuity of 20/50 or worse receiving bevacizumab had worse 2-year visual acuity outcomes compared with those taking aflibercept.8 Protocol AC, a multicenter, randomized clinical trial at 54 US clinical sites, showed that patients who first received bevacizumab and then switched to aflibercept due to nonresponse had noninferior 2-year vision outcomes compared with those taking aflibercept only.67,68

The efficacy of fixed-dose anti-VEGF regimens has been shown in clinical trials, but most clinicians use an as-needed or treat-and-extend approach to reduce treatment burden.69 Patients on the treat-and-extend treatment regimen are administered anti-VEGF at each visit, and the intervals between appointments are extended, maintained, or decreased based on the presence of macular edema, as determined by optical coherence tomography imaging.70 Treat-and-extend has been shown to have similar vision and anatomic outcomes compared with as-needed or fixed-dose regimens in patients with center-involved DME, with treat-and-extend requiring significantly fewer injections compared with fixed dosing.70,71

Extended treatment intervals can be used with other anti-VEGF agents that have received US Food and Drug Administration approval for treatment of center-involved DME.72,73 In the double-masked 96-week PHOTON (Study of a High-Dose Aflibercept in Participants With Diabetic Eye Disease) trial,74 patients with center-involved DME were randomized to receive aflibercept 8 mg every 12 or 16 weeks after 3 monthly doses or aflibercept 2 mg every 8 weeks after 5 monthly doses. Aflibercept 8 mg provided noninferior outcomes with fewer injections. In the YOSEMITE and RHINE (Efficacy and Safety of Faricimab in Participants With Diabetic Macular Edema) trials, faricimab also had extended durability in treating patients with center-involved DME.75