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Canadian Pharmacists Association
Canadian Pharmacists Association
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Chapter 30: Retinopathy

Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

Introduction
  • Diabetic retinopathy is the most common cause of new cases of legal blindness in people of working age. In the United States, 40.3% of adults have retinopathy; 8.2% have sight-threatening retinopathy.
  • Visual loss is associated with significant morbidity, including increased falls, hip fracture and a 4-fold increase in mortality.
  • Among individuals with type 1 diabetes, limb amputation and visual loss due to diabetic retinopathy are the independent predictors of early death.
Definition and Pathogenesis
  • Diabetic retinopathy is clinically defined, diagnosed and treated based on the extent of retinal vascular disease exclusively.
  • Three distinct forms of diabetic retinopathy are described:
  1. Macular edema, including diffuse or focal vascular leakage at the macula;
  2. Progressive accumulation of blood vessel change that includes microaneurysms, intraretinal hemorrhage, vascular tortuosity and vascular malformation (together known as nonproliferative diabetic retinopathy) that ultimately leads to abnormal vessel growth (proliferative diabetic retinopathy);
  3. Retinal capillary closure, a form of vascular change detected on fluorescein angiography, which is also well recognized as a potentially blinding complication of diabetes but currently has no treatment options.
Screening
  • In individuals with type 2 diabetes, screening and evaluation for diabetic retinopathy by an expert professional should be performed at the time of diagnosis of diabetes [Grade A, Level 1] and annually thereafter. The interval for follow-up assessments should be tailored to the severity of the retinopathy. In those with no or minimal retinopathy, the recommended interval is 1–2 years [Grade A, Level 1].
  • Screening for diabetic retinopathy should be performed by experienced professionals; either in person or through interpretation of retinal photographs taken through dilated pupils [Grade A, Level 1].
  • Patients with sight-threatening diabetic retinopathy should be assessed by a general ophthalmologist or retina specialist [Grade D, Consensus]. Laser therapy and/or vitrectomy [Grade A, Level 1A] and/or pharmacological intervention [Grade A, Level 1A] should be used.
    • Sight-threatening diabetic retinopathy includes severe nonproliferative diabetic retinopathy, proliferative diabetic retinopathy or clinically significant macular edema (CSME), a strictly defined form of diabetic macular edema (DME) that relies on the clinical assessment of retinal thickening based on subjective assessment of area and distance from the fovea (the centre of the macula responsible for high-acuity vision), with or without so-called hard exudates.

TABLE 1

  • Diabetic retinopathy rarely develops in children with type 1 diabetes <10 years of age regardless of the duration of diabetes.
  • Among patients <15 years of age, irrespective of age of onset of diabetes, the prevalence of mild nonproliferative retinopathy was 2%, and none had sight-threatening diabetic retinopathy.
  • However, the prevalence rate increases sharply after 5 years' duration of diabetes in postpubertal individuals with type 1 diabetes.
  • In individuals ≥15 years of age with type 1 diabetes, screening and evaluation for retinopathy by an expert professional should be performed annually starting 5 years after the onset of diabetes [Grade A, Level 1].
  • Telemedicine programs relying on fundus photography are widely used in Canada and internationally for the identification and triage of patients with diabetic retinopathy.
Delay of Onset and Progression
  • Risk factors for the development or progression of diabetic retinopathy are longer duration of diabetes, elevated glycated hemoglobin (A1C), increased blood pressure (BP), dyslipidemia, low hemoglobin level, pregnancy (with type 1 diabetes), proteinuria and severe retinopathy itself.
  • To prevent the onset and delay the progression of diabetic retinopathy, people with diabetes should be treated to achieve optimal control of blood glucose [Grade A, Level 1A] and BP [Grade A, Level 1A, for type 2 diabetes].

Glycemic control

  • Tight glycemic control, targeting an A1C ≤7%, is recommended to slow the development and progression of diabetic retinopathy.
  • The Diabetes Control and Complications Trial (DCCT) and the UKPDS demonstrated that intensive glycemic control (A1C ≤7%) reduced both the development and progression of retinopathy, with the beneficial effects of intensive glycemic control persisting for up to 10 years after completion of the initial trials.
  • Targeting an A1C ≤6.5% in patients with established type 2 diabetes may not significantly increase such beneficial effects.
  • In type 1 diabetes, rapid improvement of glycemia may be associated with transient early worsening of retinopathy, but this effect is offset by long-term benefits.

Blood pressure control

  • BP control is an important component of risk factor modification in diabetes and reduces the risk of retinopathy progression.
  • The UKPDS showed that, among patients with newly diagnosed type 2 diabetes, BP control (target BP <150/85 mm Hg, actual BP 144/82 mm Hg) resulted in a significant reduction in retinopathy progression as well as a decrease in significant visual loss and requirement for laser therapy compared to less control (target BP <180/105 mm Hg, actual mean BP 154/87 mm Hg).
  • In the Renin-Angiotensin System Study (RASS), involving 223 normotensive, normoalbuminuric participants with type 1 diabetes, neither the angiotensin-converting enzyme (ACE) inhibitor, enalapril, nor the angiotensin receptor blocker (ARB), losartan, reduced retinopathy progression independent of BP change.
  • While BP lowering (including use of RAS blockers) reduces retinopathy rates and is an important component of vascular protection, there is insufficient evidence to recommend RAS blockade as primary prevention for retinopathy for all normotensive patients with diabetes.

Lipid-lowering therapy

  • Dyslipidemia is an independent risk factor for retinal hard exudates and clinically significant macular edema (CSME) in type 1 diabetes.
  • While statin-based lipid-lowering therapies are an integral part of vascular protection in diabetes, the role of these agents in preventing the development or progression of retinopathy has not been established.
  • The role of the peroxisome proliferator-activated receptor-alpha agonist, fenofibrate, has been assessed in 2 large-scale randomized controlled trials.
    • In one study fenofibrate 200 mg daily reduced both the requirement for laser therapy and retinopathy progression among patients with pre-existing retinopathy.
    • In a second study, the addition of fenofibrate 160 mg daily to simvastatin was associated with a 40% reduction in retinopathy progression over 4 years.
    • Though not recommended for CVD prevention or treatment, fenofibrate, in addition to statin therapy, may be used in patients with type 2 diabetes to slow the progression of established retinopathy [Grade A, Level 1A].
    • The mechanism for any beneficial effect of fenofibrate in diabetic retinopathy has not been established. For more information on these studies refer to Canadian Diabetes Association Clinical Practice Guidelines: Chapter 30.

Antiplatelet therapy

  • Systematic review suggests that acetylsalicylic acid (ASA) therapy neither decreases nor increases the incidence or progression of diabetic retinopathy, nor does it appear to be associated with an increase in risk of vitreous hemorrhage or DME.
Treatment
  • Treatment modalities for diabetic retinopathy include retinal photocoagulation, intraocular injection of pharmacological agents and vitreoretinal surgery.
  • Visually disabled people should be referred for low-vision evaluation and rehabilitation [Grade D, Consensus].

Laser therapy

  • As determined in the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS), laser therapy by panretinal photocoagulation to the retinal periphery reduces severe visual loss and reduces legal blindness by 90% in people with severe nonproliferative or proliferative retinopathy and has long-term benefit.  
  • As determined by the ETDRS, focal and/or grid laser treatment to the macula for CSME reduces the incidence of moderate visual loss by 50%.

Local (intraocular) pharmacological intervention

  • In the treatment of DME with centre-involving disease, as defined by Optical Coherence Tomography (OCT) or clinical examination, intraocular pharmacotherapy is now available. With the knowledge that the cytokine vascular endothelial growth factor (VEGF) plays a primary role in the development of DME, 2 anti-VEGF drugs are now widely used.
  • Two clinical trials, using monthly ranibizumab, a humanized recombinant anti-VEGF antibody fragment, with or without prompt laser, improved visual acuity compared against sham over the 2 years of study.
  • A similar outcome was noted when comparing intraocular injection of bevacizumab (a full-length antibody against VEGF) to macular laser. Intraocular injection of bevacizumab in diabetic retinopathy constitutes off-label use of the drug in Canada.
  • Intraocular injection of steroid combined with prompt macular laser can be used to treat DME and has shown to be as effective as ranibizumab in a single subgroup of patients characterized by previous cataract surgery.
    • Treatment with intraocular steroid is associated with increased rates of glaucoma and cataract progression compared to sham.

Surgical intervention

  • The Diabetic Retinopathy Vitrectomy Study (DRVS) Group found that people with type 1 diabetes of <20 years' duration and severe vitreous hemorrhage were more likely to achieve good vision with early vitrectomy compared to conventional management.
  • Similarly, early vitrectomy was associated with higher chance of visual recovery in people with either type 1 or 2 diabetes with very severe proliferative diabetic retinopathy.
  • Vitrectomy may also be used in cases of diffuse macular edema with or without vitreomacular traction.
  • The use of perioperative ASA and warfarin therapy for persons undergoing ophthalmic surgery does not appear to raise the risk of hemorrhagic complications.
  • It is important to encourage patients with even moderate visual loss to seek assistance from community services that provide spectacle correction, enhanced magnification, vision aids and measures to encourage independence and ongoing quality of life
Table 1: Screening for Retinopathy

When to initiate screening

  • Five years after diagnosis of type 1 diabetes in all individuals ≥15 years
  • In all individuals at diagnosis of type 2 diabetes

Screening methods:

  • Seven-standard field, stereoscopic-colour fundus photography with interpretation by a trained reader (gold standard)
  • Direct ophthalmoscopy or indirect slit-lamp funduscopy through dilated pupil
  • Digital fundus photography

If retinopathy is present:

  • Diagnose retinopathy severity and establish appropriate monitoring intervals (≤1 year)
  • Treat sight-threatening retinopathy with laser, pharmacological or surgical therapy
  • Review glycemic, BP and lipid control, and adjust therapy to reach targets per guidelines∗
  • Screen for other diabetes complications

If retinopathy is not present:

  • Type 1 diabetes: rescreen annually
  • Type 2 diabetes: rescreen every 1–2 years
  • Review glycemic, BP and lipid control, and adjust therapy to reach targets per guidelines∗
  • Screen for other diabetes complications

BP, blood pressure.

∗ See the following:

Targets for Glycemic Control, p. S31

Dyslipidemia, p. S110

Treatment of Hypertension, p. S117

Type 1 Diabetes in Children and Adolescents, p. S153

Type 2 Diabetes in Children and Adolescents, p. S163

Diabetes and Pregnancy, p. S168

Return to text

For definitions of the levels of evidence cited in this chapter, please refer to the Guideline Recommendations: Levels of Evidence.

If you would like more details on this topic, please visit the Canadian Diabetes Association Clinical Practice Guidelines: Chapter 30.