Approach

The main goals of therapy are to optimize hypertensive, glycemic, and lipid control and ensure that sight-threatening disease is arrested before visual loss occurs, as visual loss is easier to prevent than to reverse. Patients should be advised to consult their physician to achieve optimal hypertensive, glycemic, and lipid control. Weight loss, exercise, and control of diet are also beneficial. Although control of blood glucose and blood pressure slows the onset and delays the progression of retinopathy, once sight-threatening disease is present, ophthalmic treatment is necessary.[48][50]​​​[53]​ Typically, this includes macular laser therapy, intravitreal therapy, panretinal photocoagulation, vitrectomy surgery, or a combination of these.[74][80][90][91][92]​​[93][94]

Criteria for specialist referral are as follows.[3][61]​​[95]​​

  • Proliferative diabetic retinopathy (PDR): requires urgent referral.

  • Moderate or worse nonproliferative diabetic retinopathy (NPDR): requires routine referral.

  • Macular edema: requires routine referral. Clinical signs include one of the following:

    • Exudate within one disk diameter of the center of the fovea, OR

    • Ring or group of exudates within the macula, OR

    • Any microaneurysm or hemorrhage within one disk diameter of the center of the fovea if associated with best corrected visual acuity of less than 6/12.

If diabetic retinopathy is present, the specialist will identify the patient’s specific subgroup on the basis of clinical signs and optical coherence tomography.

Nonproliferative diabetic retinopathy (NPDR)

NPDR with no macular edema or non-center-involving diabetic macular edema requires surveillance only. Patients should be advised to consult their physician to achieve adequate hypertensive, glycemic, and lipid control.

Patients with NPDR and center-involving diabetic macular edema with visual acuity better than 6/9 have been shown to respond equally well to macular laser therapy, intravitreal aflibercept injection, and observation.[96]​ Therefore, observation without treatment is reasonable in these patients unless visual acuity becomes worse.[96]​

Patients with NPDR and center-involving diabetic macular edema with vision ≥6/9 and <6/18 respond equally well to intravitreal aflibercept, ranibizumab, and bevacizumab injection. Visual acuity was found to improve approximately 1.4 times, on average.[35]

Patients with NPDR and center-involving diabetic macular edema with visual acuity ≥6/18 and <6/96 responded better to intravitreal aflibercept injection than to ranibizumab or bevacizumab at 1 year. At 2 years, ranibizumab and aflibercept were superior to bevacizumab, and were equally effective. Considering its area-under-the-curve superiority over ranibizumab, aflibercept is the drug of choice in this patient group. Visual acuity improved on average 1.8 times from baseline to 2 years.[97]

The principal ocular complication of any intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection (aflibercept, ranibizumab, or bevacizumab) is endophthalmitis, intraocular infection, which without prompt treatment may lead to loss of sight. It occurs following approximately 0.5% of injections.[98]

There is no definite evidence of systemic adverse effects with intravitreal anti-VEGF injection.

Proliferative diabetic retinopathy (PDR)

In patients with proliferative retinopathy, panretinal photocoagulation approximately halves the rate of severe visual loss (worse than 1/60).[74][99]​​[100][101]​

Indications for laser treatment for proliferative retinopathy include:[102]

  • Mild vessels on the optic disk (greater than one quarter to one third disk area) with vitreous or preretinal hemorrhage

  • Moderate to severe new vessels on the optic disk with or without preretinal hemorrhage

  • Moderate to severe new vessels elsewhere with vitreous or preretinal hemorrhage.

Adverse ocular effects include macular edema, restriction of visual field (in some cases severe enough to lead to the loss of driving license), glare, and loss of night vision.

Supplementary intravitreal anti-VEGF agents may improve the likelihood of neovascular regression. In all major studies examining the effect of intravitreal anti-VEGF agents on macular edema, the proportion of patients with proliferative retinopathy is small. To extrapolate the findings of these studies to patients with proliferative retinopathy and macular edema is of questionable validity, though it is common in clinical practice.[35]​

Iris neovascularization

Iris neovascularization can be identified on slit-lamp examination. However, it is nearly always associated with proliferative retinopathy. Panretinal photocoagulation is considered a matter of urgency in patients with iris neovascularization, despite only modest supporting evidence.[103]

There are no studies examining the effect of intravitreal anti-VEGF agents in the management of macular edema in patients with iris neovascularization. In clinical practice, however, the results of studies of anti-VEGF agents are commonly applied to macular edema in patients with iris neovascularization.[35][91][104]​​​

Advanced proliferative diabetic retinopathy

Patients with macular traction retinal detachment or traction-rhegmatogenous retinal detachment may benefit from vitrectomy.[105][106]​ Nonclearing vitreous hemorrhage is usually treated with vitrectomy, which is best carried out early in patients with type 1 diabetes with a diabetes duration of less than 20 years.[93][94][107]​​

One review has suggested that vitrectomy may be beneficial in patients with no or incomplete posterior vitreous detachment, vitrectomy may be beneficial.[108]​ Preoperative intravitreal bevacizumab may improve surgical outcomes.[109]

Adverse effects of vitrectomy in proliferative retinopathy include cataracts, raised intraocular pressure, entry-site neovascularization, iris neovascularization, vitreous cavity hemorrhage, retinal tear formation, retinal detachment, and endophthalmitis. Crunch syndrome, the rapid development of traction retinal detachment, may follow preoperative intravitreal anti-VEGF injection.[110]  ​

Continuing therapy

If the patient responds to anti-VEGF therapy, then it should be continued according to regimen, visual acuity, and optical coherence tomography findings.

Intravitreal aflibercept (as-needed, and as fixed loading doses followed by regular injection every two months) has been shown to be effective in patients with diabetic macular edema.[35][104]​​​​[111][112]​​​[113]

Faricimab, a bispecific angiopoietin-2 and VEGF inhibitor, was noninferior to aflibercept (mean change in best-corrected visual acuity at 1 year) in phase 3 randomized trials of patients with diabetic macular edema.[114]​ Incidence of ocular adverse events was comparable.

One systematic review and network meta-analysis found that faricimab, used in a treat and extend protocol for diabetic macular edema with intervals up to every 16 weeks, was associated with a statistically greater increase in mean change in best-corrected visual acuity compared with flexible regimens of ranibizumab and bevacizumab.[115]​ The analyses indicated that the faricimab treat and extend protocol decreased retinal thickness compared with other flexible dosing regimens (aflibercept, ranibizumab, bevacizumab, dexamethasone and laser therapy). Faricimab injection frequency was numerically lower versus other treatments using a flexible dosing regimen.[115]

In patients treated with intravitreal corticosteroid therapy, it should be continued subject to visual acuity, presence of cataract, intraocular pressure, and optical coherence tomography findings; consider switching to intravitreal anti-VEGF agents or macular laser therapy if unresponsive.

In patients treated with macular laser therapy, it should be continued according to visual acuity and optical coherence tomography findings; consider switching to intravitreal anti-VEGF agents or intravitreal corticosteroids (dexamethasone, fluocinolone acetonide) if unresponsive.

Macular edema unresponsive to intravitreal anti-VEGF therapy

The modified Early Treatment Diabetic Retinopathy Study (ETDRS) direct/grid laser photocoagulation technique may be considered for macular edema unresponsive to intravitreal anti-VEGF treatment.[116]

Adverse effects of macular laser therapy include paracentral visual loss, visible scotomata, and, occasionally, choroidal neovascularization or foveal injury.

Intravitreal corticosteroid therapy may be considered for edema unresponsive to intravitreal anti-VEGF treatment, particularly in eyes that have undergone cataract extraction.[44][117]​​ One systematic review reported that intravitreal corticosteroids may improve vision in people with diabetic macular edema compared with sham or control.[118]​ However, the effects were small, about one line of vision or less in most comparisons.[118]

Adverse effects of intravitreal corticosteroid injection include endophthalmitis, cataract, elevated intraocular pressure, and migration of implant.

Macular edema with anteroposterior vitreomacular traction

Some patients with anteroposterior vitreomacular traction benefit from vitrectomy surgery.[119]

Adverse effects of vitrectomy include cataracts, raised intraocular pressure, vitreous cavity hemorrhage, retinal tear formation, retinal detachment, and endophthalmitis.

Disease refractory to treatment

Some forms of retinopathy are profoundly refractory to therapy. These include macular ischemia, chronic macular edema, chronic macular detachment, and advanced optic atrophy from neovascular glaucoma. If both eyes are affected, such patients should be offered low vision assessment and benefits associated with visual disability.[62][87]​​[120][121]​​

Patients should be advised to consult their physician to achieve adequate hypertensive, glycemic, and lipid control.[62][87]​​​

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