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    Diabetic retinopathy

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    Sep.19.2023

    Diabetic Retinopathy

    Synopsis

    Key Points

    • Diabetic retinopathy is a vision-threatening complication of diabetes that occurs within 20 years of diagnosis in the majority of patients r1
    • Patients may present with sudden, painless vision loss; floaters; and blurry or hazy vision
    • Optimal diagnosis is made through suggestive history and findings from dilated fundus examination and digital retinal photography
    • Fluorescein angiography is useful to rule out other conditions with similar features, determine the extent of retinopathy, and guide therapy
    • Primary treatment is aimed at delaying progression or onset of retinopathy by optimizing management of diabetes and comorbidities such as hypertension or hyperlipidemia r2
      • Photocoagulation and intravitreal vascular endothelial growth factor inhibitors are reserved for some higher-risk or severe cases, especially when macular edema is present and clinically significant
      • Vitrectomy is used only when other therapies fail or when vitreous hemorrhage or traction on macula warrant it r3
    • Complications include macular edema, vitreous hemorrhage, and retinal detachment r4r5r6

    Urgent Action

    • Rapidly assess (by comprehensive eye examination with ophthalmoscopy) any patient with painless, sudden vision loss or blurry vision, which may indicate retinal/vitreous hemorrhage, retinal tear, or traction retinal detachment
    • Urgent laser photocoagulation or cryopexy is indicated for treatment of proliferative diabetic retinopathy to prevent development of complications such as vitreous hemorrhage

    Pitfalls

    • Underlying nonocular cancers (eg, lymphoma, multiple myeloma) or viral infection (eg, hepatitis C virus, cytomegalovirus) may also have findings similar to those of diabetic retinopathy and should be ruled out
    • Diabetic retinopathy may coexist with ocular ischemic syndrome, so if there is unilateral or marked asymmetry of retinopathy in a patient with diabetes, evaluate for possible carotid artery occlusive disease r7

    Terminology

    Clinical Clarification

    • Diabetic retinopathy is a microvascular complication of type 1 or type 2 diabetes mellitus, characterized by damage to the retinal blood vessels and resulting in progressive loss of vision caused by the following: r4
      • Microaneurysms
      • Blot hemorrhages
      • Exudative, ischemic, and proliferative changes
      • Macular edema

    Classification

    • Diabetic retinopathy progresses from mild nonproliferative stage to more advanced vision-threatening proliferative retinopathy, which can be complicated by neovascular glaucoma or retinal detachment r8r9
      • Diabetic macular edema can occur at any stage of diabetic retinopathy r8
    • Nonproliferative retinopathy r10
      • Mild
        • Presence of more than 1 microaneurysm
      • Moderate
        • Presence of more than 1 microaneurysm, hemorrhages, and hard protein exudates
      • Severe
        • Presence of any of the following:
          • Diffuse intraretinal hemorrhages (20 or more according to international definition)r9 and microaneurysms in all 4 quadrants
          • Venous beading in more than 2 quadrants
          • Intraretinal microvascular abnormalities in more than 1 quadrant
    • Proliferative retinopathy r11
      • Characterized by neovascularization of the disk, retina, or iris
      • Associated with vitreous hemorrhages, gliosis, traction retinal detachment, and macular edema
        • Early proliferative retinopathy
          • Neovascularization of the optic disk in less than one-third of disk area
          • Neovascularization of the optic disk without preretinal or vitreous hemorrhage
          • Neovascularization elsewhere in less than one-half of disk area and/or without preretinal or vitreous hemorrhage
        • High-risk proliferative retinopathy
          • Neovascularization of the optic disk in one-quarter to one-third of disk area
          • Neovascularization of the optic disk and preretinal or vitreous hemorrhage
          • Neovascularization in the retina outside the disk in at least one-half of disk area and preretinal or vitreous hemorrhage
        • Severe proliferative retinopathy
          • Preretinal or vitreous hemorrhage that obscures posterior fundus or central macular detachment
    • Diabetic macular edema
      • Clinically significant macular edema consists of retinal thickening with or without hard exudates involving the center of macula or close to it; this term has largely been replaced by the following terms: r9r12
        • Non–central-involved diabetic macular edema (mild) r13
          • Retinal thickening in macula that is 1 mm or greater in diameter around the fovea and does not involve the central subfield zone
        • Central-involved diabetic macular edema (severe) r13
          • Retinal thickening in macula that is 1 mm or greater in diameter and involves the central subfield zone

    Diagnosis

    Clinical Presentation

    History

    • Most patients are asymptomatic until advanced stages of disease; presentation includes history of the following: c1
      • Preexisting type 1 diabetes c2
        • More than 90% of patients with type 1 diabetes will develop diabetic retinopathy by 20 years after diagnosis r1
      • Preexisting type 2 diabetes
        • More than 60% of patients with type 2 diabetes will develop diabetic retinopathy by 20 years after diagnosis r11
    • Symptoms, when present, can include:
      • New onset of floaters, shadows, or black debris in vision due to vitreous hemorrhage r1c3c4c5
      • Impaired contrast sensitivity c6
      • Decreased visual acuity not amenable to correction with refraction c7
      • Sudden loss of vision (caused by vitreous hemorrhage or retinal detachment) c8
      • Dark curtain in vision due to detached retina r3c9

    Physical examination

    • Changes observed on stereoscopic funduscopy r14
      • Mild nonproliferative retinopathy
        • Microaneurysms: earliest clinical sign; appear as small red dots c10
        • Dot/blot hemorrhages: small, round, ruptured microaneurysms in the deeper layers of the retina (confined to the internal limiting membrane) c11c12
      • Moderate nonproliferative retinopathy
        • Microaneurysms c13
        • Dot/blot hemorrhages c14c15
        • Hard exudates: precipitated protein/lipids with a yellow, whitish, and waxy particulate matter appearance that have leaked out of the retinal capillaries with increased permeability c16
        • Macular edema: breakdown of the blood-retina barrier in the macular region, resulting in protein and fluid deposition that causes swelling and thickening of the macula c17
        • Venous beading c18
        • Cotton wool spots: infarctions in the retinal nerve fiber layer c19
      • Severe nonproliferative retinopathy
        • Marked capillary loss c20
        • Increased venous beading (retinal ischemia) c21c22
        • Multiple intraretinal hemorrhages in all 4 quadrants of the fundus c23
        • Venous beading in more than 2 quadrants c24
        • Intraretinal microvascular abnormality: shunt vessels appearing as abnormal dilation or branching of existing capillaries in more than 1 quadrant c25
      • Early proliferative retinopathy c26
        • Neovascularization in the disk area and elsewhere c27
        • Preretinal hemorrhage: rupture of new blood vessels between the retinal layers and the vitreous c28
        • Vitreous hemorrhage: rupture of new blood vessels and leakage of blood into the vitreous humor c29
        • Multiple intraretinal hemorrhages in all 4 quadrants of fundus c30
        • Venous beading in more than 2 quadrants c31
      • High-risk proliferative retinopathy
        • Neovascularization of disk area (one-quarter to one-half of the disk area) c32
        • Vitreous or preretinal hemorrhage c33c34
      • Severe proliferative retinopathy
        • Posterior fundus obscured by preretinal or vitreous hemorrhage c35
        • Central macular detachment c36
      • Clinically significant macular edema
        • Early Treatment Diabetic Retinopathy Study definition of clinically significant macular edema included: r15r16
          • Thickening of retina at or within 500 µm of the center of the macula c37
          • More than 1 disk area of retinal thickening, any part of which is within 1 disk diameter of the center of the macula
          • Hard exudates at or within 500 µm of the center of the macula with adjacent retinal thickening c38
        • Posterior fundus obscured by preretinal or vitreous hemorrhage c39
        • Central macular detachment c40
        • Macular cysts on ocular coherence tomography c41
        • Subretinal fluid on ocular coherence tomography c42

    Causes and Risk Factors

    Causes

    • Chronic hyperglycemia results in vascular leakage, angiogenesis, neuronal damage, and inflammatory insults r4c43
      • Primary contributor is chronic capillary nonperfusion and retinal ischemia r17c44
      • Injuries to the retinal neurovascular unit include: r18
        • Microaneurysms, hemorrhages, and angiogenesis c45c46c47
        • Retinal detachment c48
        • Macular edema c49
      • Specific vascular events include: r19
        • Altered microvascular permeability c50
        • Focal hypoxic events c51
        • Abnormal production of growth factors (especially VEGF [vascular endothelial growth factor]) and cytokines c52

    Risk factors and/or associations

    Age
    • Age at type 1 diabetes onset influences risk for retinopathy r20
      • Patients with onset of diabetes between the ages of 5 and 14 years are at highest risk c53c54
      • Patients with onset of diabetes between the ages of 15 and 40 years are at lowest risk c55c56
    • Younger age at type 2 diabetes onset (younger than 45 years at diagnosis) is associated with a higher prevalence and severity of retinopathy r21r22c57c58c59c60
    Sex
    • May vary by ethnicity, but overall, equally prevalent in males and females in the United States r23c61c62
    Genetics
    • Diabetic retinopathy is a polygenic disorder c63
    • Heritability is high: estimated at about 27% for any diabetic retinopathy and about 52% for proliferative diabetic retinopathy r24
    • Associated with several genes, including AKR1B1 (aldose reductase), eNOS (endothelial NOS), ICAM1 (intercellular adhesion molecule 1), VEGF, ITGA2 (α2β1 integrin), PON (paraoxonase), TNF-β (tumor necrosis factor-β), and APOEe4 (ε4 allele of the apolipoprotein E gene) r19
    Ethnicity/race
    • More prevalent in Black (38.8%) and Mexican American (34%) populations than in White populations (26.4%) r25c64c65c66c67
    Other risk factors/associations r26
    • Duration of diabetes r27c68
      • Prevalence of retinopathy increases progressively with increased duration of diabetes
      • Incidence of retinopathy among patients with type 1 diabetes approaches more than 90% at 20 years after diagnosis
      • Incidence of retinopathy among patients with type 2 diabetes is between 50% and 80% at 20 years after diagnosis
    • Hyperglycemia: increases incidence and progression of diabetic retinopathy r10r22c69
    • Hypertension: association exists between elevated blood pressure and presence of retinopathy; however, whether blood pressure causally influences development is unclear r28c70
    • Hyperlipidemia: weak association exists between serum lipid levels (largely LDL) and presence of diabetic retinopathy r27c71
    • Pregnancy: increases risk for progression of retinopathy r27c72
    • Nephropathy: closely associated with diabetic retinopathy, possibly owing to undesirable effects on lipids and platelets r28c73
    • Establishment of good glycemic control after a period of uncontrolled diabetes (paradoxical early worsening): increases risk for progression of retinopathy

    Diagnostic Procedures

    Primary diagnostic tools

    • Comprehensive eye examination and evaluation includes visual acuity testing, evaluation of intraocular pressure, pupillary assessment, dilated slitlamp examination employing biomicroscopy with a handheld lens (90 or 78 diopter) and indirect ophthalmoscopy c74
    • Dilated funduscopic examination is the primary method for detecting diabetic retinopathy r2r17c75
      • Used to examine any changes in the fundus that are suggestive of retinopathy such as retinal microaneurysms, changes in the retinal vasculature, and/or hemorrhage
      • Posterior pole and midperipheral retina are best visualized using slitlamp biomicroscopy with a handheld lens (90 or 78 diopter); peripheral retina may be examined using slitlamp biomicroscopy or indirect ophthalmoscopy r9
    • Retinal (fundus) photography is an alternative method for detecting vision-threatening diabetic retinopathy r2r29c76
      • High-resolution method of examining retina and its vasculature
      • May include 30° to wide-field, ultrawide-field, monophotography, stereophotography, and dilated or undilated photography r8
      • Most cases of clinically significant diabetic retinopathy can be detected in this manner and it is particularly useful where there is limited access to ophthalmologists r2r17
      • Can also be used to document severity of diabetes, presence of neovascularization, and need for additional treatment r9
      • Considered a highly accurate, time- and cost-effective method of fundus assessment; however, it is not a substitute for comprehensive eye examination as described above r17
    • Ancillary testing may include the following:
      • Optic coherence tomography r9c77
        • Not used for screening but may be used to evaluate unexplained visual acuity loss in patients with diabetic retinopathy. It is the standard tool for guiding management of patients diagnosed with diabetic retinopathy
      • Fluorescein angiography c78
        • Not routinely necessary at time of diagnosis or for evaluating patients with no or minimal nonproliferative diabetic retinopathy
        • Used to examine circulation of blood within blood vessels of the retina and aid in diagnosis of macular edema and proliferative diabetic retinopathy r9
      • Optic coherence tomography angiography r9c79
        • Emerging noninvasive technology that is useful for detecting areas of intraretinal microvascular anomalies and neovascularization r17r30r31
        • Preclinical microvascular changes and macular nonperfusion, which may correlate to severity of diabetic retinopathy, can be detected r9
      • B-scan ultrasonography r9c80
        • Useful to assess retina and detect retinal detachment in cases of vitreous hemorrhage or other media opacity
    • Evaluation should also include assessment or review of blood pressure and laboratory parameters such as hemoglobin A1C, lipid levels, and renal function r8c81c82c83

    Imaging

    • Optic coherence tomography r32c84
      • Noninvasive technology that provides high-resolution mapping of the vitreoretinal interface, neurosensory retina, and subretinal space r9r33
      • Used to quantify retinal thickness and detect macular edema, vitreomacular traction, and other forms of macular disease r9
      • Often used to guide therapeutic decisions when changes are made to existing treatments (eg, repeat anti-VEGF injections versus starting laser treatment) r9

    Procedures

    IV fluorescein angiography r34r35c85
    General explanation
    • Fluorescent dye (fluorescein), delivered by IV injection, highlights the retinal vasculature; image is captured by a retinal camera
    • Used to detect areas of retinal ischemia and leaking microaneurysms before laser photocoagulation treatment of eyes with clinically significant macular edema
    • Useful to differentiate diabetic macular swelling from other macular disease or for evaluation of a patient with unexplained vision loss r9
    Indication
    • To exclude conditions such as retinal/arterial vein occlusions, tumors, macular degeneration, or hereditary retinal diseases
    • To determine if laser therapy is indicated
    Contraindications
    • Known allergy to dyes, iodine, or shellfish
    • History of anaphylaxis in response to fluorescein
    • Severe renal impairment
    • First trimester of pregnancy is a relative contraindication because fluorescein is a pregnancy risk category C compound r36r37r38
    Complications
    • Anaphylaxis (rare) r39
    Interpretation of results
    • Hyperfluorescence: indicates vessel leakage caused by microaneurysms, retinal edema, or neovascularization
    • Hypofluorescence: indicates vessel blockage or areas blocked by the presence of exudates and/or blood

    Other diagnostic tools

    • Ocular telehealth programs c86
      • Nonmydriatic camera used for retinal imaging and remote evaluation of images at a telemedicine reading center are being used as a screening strategy for diabetic retinopathy in some geographic areas where qualified ophthalmologists are not available; systems using artificial intelligence are also available r29r40
      • Screening results obtained from nonmydriatic camera images and assessed through telemedicine are generally in agreement with findings from dilated fundus photography r41
      • Retinal photography may serve as a screening tool for retinopathy but is not a substitute for in-person comprehensive eye examination, which is recommended for first evaluation and for follow-up when abnormalities are detected r2

    Differential Diagnosis

    Most common

    • Central retinal vein occlusion r7c87d1
      • Occlusion of the retinal vasculature resulting in visual loss similar to that of diabetic retinopathy
      • Differentiate using stereoscopic fundus examination
        • Retinal veins are dilated and tortuous in central vein occlusion, whereas they are dilated and beaded in diabetic retinopathy
        • Microaneurysms and hard exudates are uncommon in central retinal vein occlusion, whereas they are common in diabetic retinopathy
        • Optic disk is swollen in central retinal vein occlusion
      • Differentiate using IV fluorescein angiography
        • Prolonged arteriovenous transit time is observed in central retinal vein occlusion, whereas arteriovenous transit time is within the reference range in diabetic retinopathy
    • Ocular ischemic syndrome r7c88
      • Ocular hypoperfusion caused by stenosis or occlusion
      • Both diabetic retinopathy and ocular ischemic syndrome present with visual loss, but pain occurs in up to 40% of patients with ocular ischemic syndrome r42r43
      • Differentiate using stereoscopic fundus examination
        • Retinal veins are dilated but nontortuous in optic ischemic syndrome, whereas they are dilated and beaded in diabetic retinopathy
        • Microaneurysms are observed in the midperiphery in optic ischemic syndrome, whereas they are located in the posterior pole in diabetic retinopathy
        • Hard exudates are not observed in optic ischemic syndrome, whereas they are common in diabetic retinopathy
      • Differentiate using IV fluorescein angiography
        • Macular edema is rarely observed in optic ischemic syndrome, whereas it is common in diabetic retinopathy
        • Delayed and patchy choroidal filling is observed in optic ischemic syndrome, whereas choroidal filling is usually normal in diabetic retinopathy
    • Valsalva retinopathy r44c89
      • Preretinal hemorrhages caused by a sudden increase in intrathoracic pressure
      • Subconjunctival hemorrhages may be present
      • Typically unilateral but may be bilateral
      • Differentiate using optic coherence tomography
        • Hemorrhage located in subhyaloid or subinternal limiting membrane space
    • Sickle cell retinopathy r45c90d2
      • Ischemia of the retina associated with existing sickle cell disease
      • Consequent vitreous hemorrhage and retinal detachment can lead to irreversible vision loss, similar to diabetic retinopathy
      • In sickle cell disease, retinopathy is often associated with anterior uveitis
      • Differentiate using optic coherence tomography
        • Macular ischemia with retinal thinning is consistent with sickle cell retinopathy
    • Radiation retinopathy c91
      • Complication of radiation that may present with macular edema and vitreous hemorrhage, similar to diabetic retinopathy
      • Unlike diabetic retinopathy, characterized by a loss of vascular endothelial cells while sparing the pericytes
      • Differentiate by a recent history of radiation therapy

    Treatment

    Goals

    • Prevent onset of retinopathy by optimizing metabolic and blood pressure control (primary prevention) r2
    • Delay progression of retinopathy r2
    • Preserve and improve vision r46

    Disposition

    Recommendations for specialist referral

    • Refer to an ophthalmologist for initial screening and diagnosis of diabetic retinopathy and when there is any nonproliferative diabetic retinopathy, proliferative retinopathy, or macular edema r9
    • Consult an ophthalmologist urgently for sudden loss of vision, which may be caused by vitreous/retinal hemorrhage or retinal detachment r47
    • Refer patients with low vision (those with visual acuities less than 20/40, scotomas, field loss, or contrast loss) to vision rehabilitation services r9

    Treatment Options

    Treatment strategies include medical, intravitreal, laser, and surgical approaches r28

    • Choice of treatment is individualized depending on type of retinopathy and patient and physician preferences r9
      • Treatment may be deferred until visual acuity is affected in patients with central-involved diabetic macular edema and no vision loss r48
      • Intravitreal anti-VEGF (vascular endothelial growth factor) agents are the recommended treatment for central-involved diabetic macular edema with vision loss r29
        • May be a reasonable alternative to panretinal laser photocoagulation for some patients with proliferative diabetic retinopathy
      • Focal laser photocoagulation surgery is the preferred treatment of non–central-involved diabetic macular edema
      • Focal or grid laser photocoagulation and intravitreal injections of corticosteroid are appropriate treatments for diabetic macular edema refractory to anti-VEGF therapy or for patients who are not candidates for the first line treatment r49
      • Panretinal laser photocoagulation surgery is the preferred treatment for proliferative diabetic retinopathy and in some cases for severe nonproliferative diabetic retinopathy r29
    • Medical therapy
      • For all patients, optimize glycemic control, treat dyslipidemia, and lower blood pressure to reduce the risk of retinopathy or slow its progression; however, these measures do not ameliorate vision impairment r4r12
        • Pharmacologic therapy for diabetes
          • Intensive diabetes management with the goal of achieving near-normoglycemia can prevent or delay onset and progression of diabetic retinopathy r50r51
            • General hemoglobin A1C target to strive for is 7% or less (American Diabetes Association) or 6.5% to 7.5% (International Diabetes Federation) r13r29
          • Note: a period of very strict glycemic control with rapid reduction in hyperglycemia can temporarily worsen retinopathy in patients with more severe retinopathy and/or very poor glycemic control r52
        • Antihypertensive drugs
          • Measures to control blood pressure have a greater effect on preventing incident diabetic retinopathy, rather than slowing progression r53
          • However, ACE inhibitors and angiotensin receptor blockers are effective in reducing progression of preexisting diabetic retinopathy r54
          • Aggressive attempts to achieve tight targets (systolic blood pressure less than 120 mm Hg) do not provide greater benefits r50
        • Lipid-lowering therapies
          • Addition of fenofibrate to lipid-lowering therapy may slow progression of retinopathy, particularly with very mild nonproliferative diabetic retinopathy at baseline r13r55
    • Intravitreal agents
      • First line for patients with macular edema if edema involves the center of the macula (central-involved macular edema)
      • VEGF inhibitors
        • For most patients with central-involved macular edema, VEGF inhibitors are first line agents and are preferred over focal laser photocoagulation r9
        • Can consider VEGF inhibitors for management of proliferative diabetic retinopathyr56 as an adjunct or alternative to panretinal photocoagulation, especially if both proliferative diabetic retinopathy and central-involved macular edema are present r2r30
          • VEGF inhibitors may be more effective than panretinal photocoagulation alone in the short term; however, they are associated with higher cost and risk of loss to follow-up resulting in delayed treatment and significant progression of disease r57
          • Among patients with vitreous hemorrhage secondary to proliferative diabetic retinopathy, there was no significant difference in visual acuity after initial treatment with intravitreous aflibercept compared with vitrectomy with panretinal photocoagulation r58
        • Comparison of agents
          • All available VEGF inhibitors—aflibercept, bevacizumab, brolucizumab, and ranibizumab—are effective in reducing diabetic retinopathy, provided that they are administered every 4 to 8 weeks r9r59r60
            • For central-involved macular edema and visual acuity of 20/40 or better, aflibercept, bevacizumab, and ranibizumab improved visual acuity to a similar extent r61
              • Aflibercept is most effective at improving vision when visual acuity is 20/50 or worse r61r62
            • Aflibercept confers advantage over ranibizumab and bevacizumab for improving vision in the presence of diabetic macular edema assessed at 1 year; longer-term effects are still unknown r62
          • Faricimab, an antibody that inhibits both VEGF and angiopoietin-2 pathways, is also effective and may be dosed at extended intervals of 8 to 16 weeks r9r63
      • Intravitreal corticosteroids r64
        • Approved for central-involved macular edema but typically used as second line treatment (after VEGF inhibitors) for those whose condition responds insufficiently to a series of anti-VEGF injections r29
        • Intravitreal corticosteroids are appropriate for pseudophakic eyes or for patients being considered for cataract surgery in the near future
        • Risks include cataract progression, elevation of intraocular pressure, and endophthalmitis
    • Laser photocoagulation therapy r3
      • Focal photocoagulation is used for patients with clinically significant macular edema
        • Preferred treatment of non–central-involved diabetic macular edema and mild visual impairment r9r13
      • Panretinal photocoagulation is the cornerstone treatment for high-risk and severe proliferative diabetic retinopathy r19
        • Can be considered for some cases of early proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy
    • Surgical treatment
      • Vitrectomy is indicated for severe diabetic retinopathy in the following circumstances: r3
        • Unresponsive to photocoagulation
        • Unresponsive to intravitreal VEGF inhibitors
        • Associated with vitreous hemorrhage
        • Vitreomacular traction
        • Traction retinal detachments threatening the macula and combined traction-rhegmatogenous retinal detachments r17

    Drug therapy c92

    • Antihypertensives c93
      • ACE inhibitors c94
        • Reduce risk of progression of mild to moderate nonproliferative diabetic retinopathy (by 65%) in patients with type 1 diabetes r65
        • Enalapril c95
          • Enalapril Maleate Oral tablet; Adults: 10 mg PO once daily. Dose range: 5 to 20 mg/day PO in 1 or 2 divided doses. Usually begin with a low dose and titrate to response and tolerance.
      • Angiotensin receptor blockers c96
        • Losartan c97
          • Reduces risk of progression of mild to moderate nonproliferative diabetic retinopathy (by 65%) in patients with type 1 diabetes r65
          • Losartan Potassium Oral tablet; Adults: 50 mg PO once daily, initially. Adjust dose based on blood pressure and serum creatinine and potassium concentrations every 2 to 4 weeks up to the maximum tolerated dose. Max: 100 mg/day in 1 or 2 divided doses.
        • Candesartan c98
          • Reduces incidence of diabetic retinopathy in patients with type 1 diabetes r66
          • May enable regression of existing nonproliferative diabetic retinopathy in patients with type 2 diabetes r67
          • Candesartan Cilexetil Oral tablet; Adults: Initially, 16 mg PO once daily, unless the patient is volume-depleted. The dosage range is 8 to 32 mg/day PO, given in 1 to 2 divided doses.
    • VEGF inhibitors c99
      • Aflibercept r68c100
        • Indicated for treatment of central-involved macular edema related to diabetic retinopathy or for proliferative diabetic retinopathy
        • Shown to improve visual acuity by gain in reading ability of more than 15 letters in 31.1% to 41.6% of patients with macular edema caused by diabetic retinopathy when compared with macular laser photocoagulation (7.8%-9.1%)
        • Aflibercept Solution for injection; Adults: 2 mg (0.05 mL) by intravitreal injection in the affected eye(s) every 4 weeks for 5 months, then 2 mg (0.05 mL) by intravitreal injection in the affected eye(s) every 8 weeks. Some patients may require every 4 week dosing after the first 5 months. However, additional efficacy was not demonstrated in most patients when administered every 4 weeks vs. every 8 weeks.
      • Ranibizumab r60c101
        • Indicated for the treatment of central-involved macular edema related to diabetic retinopathy or in the treatment of high-risk proliferative diabetic retinopathy
        • Shown to improve visual acuity and reduce macular edema but requires frequent injections
        • Ranibizumab provides superior visual outcomes compared with focal laser for the treatment of diabetic macular edema r69r70
        • Ranibizumab Solution for injection; Adults: 0.3 mg by intravitreal injection in the affected eye(s) once monthly.
      • Bevacizumab r60r71c102
        • Off-label use for treatment of central-involved macular edema related to diabetic retinopathy r12
        • Actions/effects of ranibizumab and bevacizumab are comparable
        • Bevacizumab Intraocular solution; Adults: 1.25 mg by intravitreal injection in the affected eye(s).
    • Corticosteroids c103
      • Intravitreal triamcinolone acetonide r72c104
        • Off-label use for treatment of diabetic retinopathy
        • Improvement in visual acuity shown to be inferior to treatment with focal or panretinal photocoagulation
        • Associated with higher risk of increased intraocular pressure, need for glaucoma medications, and need for glaucoma surgery
          • Triamcinolone Acetonide Suspension for injection [Ocular Indications]; Adults: Dosage not established. 4 mg by intravitreal injection in the affected eye(s) has been used.
      • Implantable fluocinolone acetonide r73c105
        • Indicated for patients who have been previously treated with a course of intravitreal corticosteroids without experiencing clinically significant rise in intraocular pressure
        • Shown to improve visual acuity by gain in reading ability of more than 15 letters in 31.9% to 33% of patients treated with implantable fluocinolone acetonide compared with 21.4% of patients treated with sham procedure
        • Fluocinolone Acetonide Implant; Adults: 0.19 mg implant by intravitreal injection in the affected eye(s).
      • Implantable dexamethasone (corticosteroid) r74c106
        • Indicated for the treatment of macular edema related to diabetic retinopathy in adult patients with pseudophakia
        • Shown to improve visual acuity by gain in reading ability of more than 15 letters in 18.4% to 22.2% of patients treated with implantable dexamethasone compared with 12% of patients treated with sham procedure
        • Dexamethasone Implant; Adults: 0.7 mg implant by intravitreal injection in the affected eye(s).

    Nondrug and supportive care

    Encourage lifestyle measures that optimize glycemic control, blood pressure, and cholesterol in optimal range to delay progression or prevent onset of retinopathy r3c107c108c109

    Physical activity c110

    • Vigorous aerobic or resistance exercise may be contraindicated if proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy is present because there is risk of triggering vitreous hemorrhage or retinal detachment r75
    Procedures
    Laser retinal photocoagulation r72c111
    General explanation
    • Panretinal: hundreds of small laser burns are used to cauterize the peripheral retina to reduce ischemia
    • Focal: cauterization of specific microaneurysms near the macula to reduce plasma leakage and intraretinal swelling
    Indication
    • Proliferative diabetic retinopathy
    • Patients with clinically significant macular edema r3
    • Severe nonproliferative retinopathy, particularly in patients with type 2 diabetes
    Complications
    • Panretinal r76
      • Corneal abrasions
      • Visual field loss
      • Reduced color vision
      • Reduced contrast sensitivity
    • Focal r9
      • Laser scars
      • Paracentral scotomas
      • Choroidal neovascularization
    Interpretation of results
    • Laser photocoagulation reduces the chance of visual loss and increases the likelihood of attaining partial to complete resolution of diabetic macular edema, compared with no intervention r77
    Vitrectomy r27r78c112
    General explanation
    • Partial or complete surgical removal of vitreous humor (typically blood from a vitreous or retinal hemorrhage)
      • Allows for examination and further treatment of the posterior ocular pole
    Indication
    • Removal of vitreous hemorrhage
    • Repair of traction retinal detachment
    Complications
    • Neovascular glaucoma r79
    • Cataracts r80
    • Vitreous hemorrhage r80
    • Epiretinal membrane r80

    Special populations

    • Pregnant patients r81
      • Retinopathy is known to worsen during pregnancy and may or may not regress post partum
      • Counsel females with preexisting type 1 or type 2 diabetes who are planning to become pregnant or who are pregnant about risk of development or progression of diabetic retinopathy r29
      • Eye examinations are ideally done before pregnancy or in the first trimester for patients with preexisting type 1 or type 2 diabetes
      • Consider laser photocoagulation earlier in management of pregnant patients with proliferative diabetic retinopathy
  • Treatment options according to severity of diabetic retinopathy.ME, macular edema; VEGF, vascular endothelial growth factor.Data from American Academy of Ophthalmology Retina/Vitreous Preferred Practice Pattern Panel: Preferred Practice Pattern: Diabetic Retinopathy 2019. AAO website. Published 2019. Accessed March 13, 2022. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp
    Severity of retinopathyMacular edemaPanretinal laser photocoagulationFocal laser photocoagulationIntravitreal anti-VEGF
    No or minimal nonproliferative diabetic retinopathyNoNoNoNo
    Mild nonproliferative diabetic retinopathyNoNoNoNo
    Non–central-involved MENoSometimesNo
    Central-involved MENoRarelyUsually
    Moderate nonproliferative diabetic retinopathyNoNoNoNo
    Non–central-involved MENoSometimesRarely
    Central-involved MENoRarelyUsually
    Severe nonproliferative diabetic retinopathyNoSometimesNoSometimes
    Non–central-involved MESometimesSometimesSometimes
    Central-involved MESometimesRarelyUsually
    Proliferative diabetic retinopathy
    Early proliferative diabetic retinopathyNoSometimesNoSometimes
    Non–central-involved MESometimesSometimesSometimes
    Central-involved MESometimesSometimesUsually
    High-risk proliferative diabetic retinopathyNoRecommendedNoSometimes
    Non–central-involved MERecommendedSometimesSometimes
    Central-involved MERecommendedSometimesUsually

    • Monitoring

    • General monitoring r29
      • Follow-up intervals depend on severity of retinopathy and presence of macular edema
      • If there is no evidence of retinopathy for 1 or more annual eye examinations and glycemia is well controlled, refer the patient to an ophthalmologist or optometrist for dilated and comprehensive eye examinations every 1 to 2 years r82c113c114c115
      • If any level of diabetic retinopathy is present, refer to an ophthalmologist or optometrist for subsequent dilated retinal examinations at least annually
      • If retinopathy is progressing or threatening vision, examinations are required more often
      • Follow-up intervals for established retinopathy.Data from American Academy of Ophthalmology Preferred Practice Patterns Retina/Vitreous Panel et al: Diabetic retinopathy PPP 2019. AAO website. Published 2019. Accessed March 13, 2022. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp
        Severity of retinopathyPresence of macular edemaTime interval to follow-up (months)
        Nonproliferative diabetic retinopathy
        Non–central-involved ME3-6
        Mild nonproliferative diabetic retinopathyNo12
        Central-involved ME1
        Moderate nonproliferative diabetic retinopathyNo12
        Non–central-involved ME3-6
        Central-involved ME1
        Severe nonproliferative diabetic retinopathyNo3-4
        Non–central-involved ME2-4
        Central-involved ME1
        Proliferative diabetic retinopathy
        Early proliferative diabetic retinopathyNo3-4
        Non–central-involved ME2-4
        Central-involved ME1
        High-risk proliferative diabetic retinopathyNo2-4
        Non–central-involved ME2-4
        Central-involved ME1
    • Monitoring after intravitreal injections
      • After anti–vascular endothelial growth factor or corticosteroid injections, monitor the patient monthly for elevation in intraocular pressure and endophthalmitis r9
    • Monitoring after laser photocoagulation
      • Ophthalmology follow-up occurs 3 to 4 months after laser surgery to monitor for choroidal neovascularization r9
    • Monitoring during pregnancy
      • Monitor pregnant patients every trimester and for 1 year post partum as indicated by degree of retinopathy r29

    Complications and Prognosis

    Complications

    • Clinically significant macular edema associated with diabetic retinopathy r4c116
      • Can occur at any stage of retinopathy (nonproliferative or proliferative)
      • Leading cause of blindness in patients with diabetes
    • Vitreous hemorrhage r6c117
    • Retinal detachment r5c118
    • Glaucoma r83c119

    Prognosis

    • Improvement in and maintenance of vision correlate with optimal management of underlying diabetes and/or coexisting hypertension/hyperlipidemia r27
      • Appropriate treatment can prevent severe vision loss in 90% of cases r3
    • Increased risk of progression to proliferative retinopathy is seen in patients with: r84
      • Increased hemoglobin A1C levels
      • Renal impairment
      • Younger age at diagnosis of diabetes
      • Elevated triglyceride levels
      • Increased retinal venular diameters (in patients with type 1 diabetes) 
    • Patients with diabetic retinopathy have increased risk of morbidity and mortality owing to increased incidence of cardiovascular events (eg, myocardial infarction, stroke) compared with patients without retinopathy r85

    Screening and Prevention

    Screening

    At-risk populations

    • Patients with type 1 diabetes
      • Begin screening (by an ophthalmologist) within 3 to 5 years after onset of diabetes r2
    • Patients with type 2 diabetes
      • Refer for comprehensive ophthalmic examination at the time of diagnosis r2
    • Pregnant patients with preexisting type 1 or type 2 diabetes
      • Refer to an ophthalmologist each trimester and follow closely until 1 year post partum as indicated by degree of retinopathy r2
    • Schedule for retinopathy screening
      • After initial examination, if retinopathy is identified, refer for an annual dilated and comprehensive eye examination
      • After initial examination, in the absence of any findings of retinopathy, refer for a dilated and comprehensive eye examination every 2 years
      • Individualized schedules for retinopathy screening (based on the current state of retinopathy and hemoglobin A1C level) may reduce the frequency of eye examinations without delaying the diagnosis of clinically significant disease; however, this approach has not been fully adopted by professional society guidelines r86

    Screening tests

    • Comprehensive evaluation by an ophthalmologist includes visual acuity testing, evaluation of intraocular pressure, pupillary assessment, dilated slitlamp examination employing biomicroscopy with a handheld lens (90 or 78 diopter), and direct or indirect ophthalmoscopy r8r9c120c121
    • Other additional testing may include optic coherence tomography and fluorescein angiography r11c122c123
    • In areas where qualified eye care professionals are not readily available, retinal photography with remote reading by expert ophthalmologists or interpretation by artificial intelligence systems can be a substitute screening strategy for diabetic retinopathy r49r87
      • This type of telemedicine screening needs to be followed with timely referral for a comprehensive eye examination if abnormalities are identified
      • Artificial intelligence systems should not be used for screening patients with known retinopathy, prior treatment of retinopathy, or visual impairment r29
      • Retinal and fundus photography (digital or color film) are not substitutes for a comprehensive eye examination, which should be performed at least initially r2

    Prevention

    • Intensive diabetes management with the goal of achieving near-normoglycemia reduces the risk of developing retinopathy and slows its progression in type 1r51 and type 2r50 diabetes c124
      • Reduces ocular surgery rates for patients with type 1 diabetes r88
    • Lowering blood pressure (systolic less than 140 mm Hg) slows progression of retinopathy in type 2 diabetes r53c125
      • Aggressive lowering of systolic blood pressure to less than 120 mm Hg does not provide further benefit in retinopathy r50
    • Treatment of dyslipidemia with fenofibrate slows progression of retinopathy by up to 40% among those with nonproliferative retinopathy r55c126
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