This article is based on presentations given by Professor Emily Chew at the Australian National Health and Medical Research Council’s 2017 Masterclass: 8th Update on Diabetes and Vascular Disease held in Sydney. Diabetic retinopathy (DR) is a leading cause of preventable blindness in the working age population of Australia and is a significant health threat worldwide.1Over one-third of the world’s population with diabetes are estimated to have diabetic retinopathy, and one third of these have vision threatening retinopathy.2 Another major cause of vision loss in diabetic patients is diabetic macular oedema (DME) which can occur any time during the progression of DR. DR may progress from a non-proliferative (NPDR) stage to a proliferative (PDR) advanced stage, named for the absence or presence of abnormal new blood vessels emanating from the retina. DR can further be classified by severity. In patients with PDR, if left untreated, 50% would experience severe blindness within five years.3
Treatments for DR
Pan-retinal photocoagulation (PRP) to destroy the abnormal retina has been the mainstay of treatment for severe PDR for some time reducing the risk of severe vision loss by 95% compared with no laser photocoagulation treatment for PDR.4 However PRP can cause negative side effects such as field loss and night vision blindness. Vitrectomy is another “end stage treatment” for patients with vitreous haemorrhage that is non-clearing. For diabetic macular oedema, intraocular vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab, ranibizumab and aflibercept have been widely studied since VEGF was detected in samples of ocular fluid in patients undergoing intraocular surgery for PDR and other retinal disorders.5 Where previous treatments prevented further vision loss, ranibizumab has been suggested in a clinical trial of up to two years, to improve visual acuity compared with PRP, and result in fewer eyes developing DME or undergoing vitrectomy.6 However, the burden of ocular injections with VEGF inhibitors is high for the patient with potentially monthly injections. Furthermore, the cost of treatment with ranibizumab and aflibercept can be prohibitive.
Systemic Risk Factors associated with DR
The key risk factors for DR are elevated blood glucose levels, hypertension and
serum lipid levels.
Several randomized controlled clinical trials have investigated the effects of intensive glycaemic control on DR including the Diabetes Control and complications Trial (DCCT,1993) and the observational Epidemiology of Diabetes Intervention and Complications (EDIC, 2015) Study for Type 1 diabetes. 7-9 For Type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS, 1998) and the Veterans Administration Diabetes Trial (VADT, 2009) showed the benefit of intensive glycaemic control in the reduction of DR.10, 11
Evidence for the role of intensive blood pressure (BP) control is also derived from the UKPDS and in addition, the Actions to Control Cardiovascular Risk (ACCORD) studies.12-14 Furthermore, the ACCORDLipid and Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) studies both show how intensive lipid control is crucial for the management of DR. 12, 15
Type 1 diabetes and DR
Patients with type 1 diabetes were recruited into DCCT to examine whether intensive glucose control could decrease the development and progression of DR.7 Patients in the primary prevention cohort did not have retinopathy and those in the secondary prevention cohort already had mild retinopathy. Within each cohort patients were randomized to receive either intensive or conventional glucose lowering treatment. The appearance and progression of retinopathy and other microvascular and neurologic complications were assessed regularly for a period of 6.5 years. In the primary prevention cohort, intensive glucose therapy reduced the adjusted mean risk for the development of retinopathy by 76% (p<0.001). In the secondary prevention cohort, the need for photocoagulation was reduced by 56% (p=0.002). There were too few cases of DPR, severe NDPR or clinically important DME in the primary prevention group to draw conclusions. Additionally, the number of complications such as neuropathy and nephropathy were also decreased. 7 The DCCT study was later extended into the EDIC study which followed the natural history of participants from the DCCT study with a median of 23 years of follow-up.8, 9 The reduction in PDR risk based on the time to first occurrence of progression of retinopathy (defined as a 3-step or more progression from the level of retinopathy at the end of the DCCT), continued for four years at 71% (p<0.001) in the EDIC study, after 10 years this rate diminished to 56% (p<0.001) and after 23 years, intensive therapy was associated with a reduction in the risk of any diabetes related ocular surgery by 48% (p<0.001).8, 9 The risk of all cataract surgery was significantly reduced by 37% (p=0.01) in the intensive glucose-lowering group and the risk of retinal detachment surgery / vitrectomy was reduced by 45% (p=0.01). These results demonstrated the long-lasting effect of intensive glucose-lowering. Additionally, a reduction in the risk of cardiovascular events of 42% (p=0.02) was observed after 17 years. The risk of non-fatal myocardial infarction, stroke and cardiovascular death were also reduced by 57%(p=0.02).16
Type 2 diabetes and DR
Patients with newly diagnosed type 2 diabetes were randomised in the UKPDS to either conventional therapy with dietary restriction or intensive blood glucose treatment with either sulfonylurea or insulin or, in overweight patients, metformin, for glucose control.10
Compared with the conventional group, the risk in the intensive group was 12% lower (p=0.029) for any diabetes related endpoint; but not significant for any diabetes-related death or for all-cause mortality. Most of the risk reduction in the any diabetes related aggregate endpoint was due to the risk reduction of microvascular complications (including the need for laser photocoagulation) by 25% (p=0.0099).17 The study also found that for every 1% decrease in HbA1c, there was an approximately 35% reduction in the risk of microvascular complications.18
Aside from glycaemia, the association between raised lipid levels and DR stemmed from observational data in the Early Treatment DR Study (ETDRS) and the DCCT.7, 19 These studies suggested increased serum lipids increases risk of proliferative disease, increases risk of eye disease, and in terms of vision loss macular oedema is markedly increased, so lowering lipids seems to make sense.
The main FIELD study was a 5-year randomised, placebo-controlled study of 9,795 patients with type 2 diabetes treated with fenofibrate. Published in the FIELD ophthalmology sub-study, fenofibrate 200 mg daily (bioequivalent to 145mg) decreased the need for laser photocoagulation by about one third (HR: 0.69; 95% CI, 0.56 to 0.84; p=0.0002) compared to the placebo group.15 In patients with DR at baseline, the risk of progression defined by 2-step progression on the EDTRS scale, was lower in the fenofibrate group than placebo group (RR 4.7, 95% CI 1.4 to 15.9, provided by Prof. Chew).
Following on from FIELD, the ACCORD trial was designed to investigate the reduction of cardiovascular disease in 10,251 participants with type 2 diabetes.12, 20 The study design examined the impact of intensive glycaemic treatment, with a target of HbA1c less than 6% compared to standard glycaemic treatment (HbA1c target between 7% and 7.9%); dyslipidaemia (160mg daily, bioequivalent to 145mg of fenofibrate plus simvastatin or placebo plus simvasta tin); and systolic blood pressure control (target, <120 or <140 mm Hg).
In the ACCORDGlycemia arm, the odds ratio for the reduction of DR was significant for tight glycaemic control (OR 0.67; 95% CI, 0.51 to 0.87; p=0.003).21 In ACCORDLipid, 6.5% of participants receiving lipid lowering therapy with fenofibrate and simvastatin had progression to DR compared to 10.2% receiving placebo.12 The RR of DR progression for fenofibrate compared with placebo based on 3-step progression on the ETDRS scale, was 1.6 (95% CI, 1.1 to 2.3, provided by Prof
Chew). The ACCORD studies demonstrated intensive glycaemic control and lipid-lowering therapy in type 2 diabetic patients reduced the proportion of patients whose DR progressed by about one-third and the effects were consistent across all
subgroups, as explained by Prof Chew.
Furthermore, in FIELD and ACCORD, patients with DR at baseline saw the most
benefit from treatment with fenofibrate.
Recently, the ACCORDION-Eye study (2016) investigated whether the beneficial effects seen in ACCORD persisted for up to four years after the trial closeout.22 Four years after completing the study participants in both groups had similar HbA1c levels. There was a legacy effect of glycaemic control on progression of DR after eight years, with a 5.8% rate of DR progression with intensive treatment compared to 12.7% in the standard treatment group (adjusted OR 0.42, 95% CI,
0.28-63; P<0.0001). These findings echoed those of the DCCT/EDIC and UKPDS which showed a 10-year legacy effect of glycaemic control on DR progression. As per ACCORDION-Eye, fenofibrate treatment is beneficial for reducing the progression of DR in people with type 2 diabetes and existing DR and requires continued use to maintain the benefit.
Unfortunately, there is still limited clinical use of fenofibrate for preventing progression of DR in clinical practice.
Ophthalmologists rarely initiate oral therapy with fenofibrate, oral treatment is usually prescribed by the GP or endocrinologist.
Further education about the ACCORD and FIELD studies is needed to highlight the importance of intensive glycaemic control. In particular, the use of intensive glycaemic control for newly diagnosed patients since the beneficial effects may last for years. People with existing DR should also be considered for treatment with fenofibrate by ophthalmologists. Further research is needed into emerging oral treatments for DR.
Editorial support for the development of this article was funded by Mylan Health Pty Ltd.
The authors thank Katie Burslem, CMPP of WriteSource Medical Pty Ltd, Sydney, Australia, for providing medical writing support, which was funded by Mylan Health Pty Ltd in accordance with Good Publication Practice (GPP3) guidelines (http://www.
- Macular Disease Foundation of Australia. Diabetic Retinopathy. Accessed: September 2017. Available from: https://www.mdfoundation.com.au/content/diabetic-retinopathy-about.
- Gardne TW, Chew EY. Future opportunities in diabetic retinopathy research. Current opinion in endocrinology, diabetes, and obesity 2016; 23:91-6.
- Department of Health (UK). Diabetic Retinopathy Screening. Avaiable from
http://webarchive.nationalarchives.gov.uk/20130124042517/http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_083899.pdf Accessed 19 October 2017.
- Chew E. Presentation: Oral Therapies for Diabetic Retinopathy. 23 July 2017
- Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331: 1480-7.
- Gross JG, Glassman AR, Jampol LM, et al. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA 2015; 314:2137-46.
- Nathan DM, Genuth S, Lachin J, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in
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- DCCT EDIC Research Group. Intensive diabetes therapy and ocular surgery in type 1 diabetes. N Engl J Med 2015;372: 1722-33.
- White NH, Sun W, Cleary PA, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol 2008; 126: 1707-15.
- UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53.
- Duckworth W, Abraira C,Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-39.
- Accord Study Group, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1563-74.
- UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703-13.
- Accord Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1575-85.
- Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for
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- Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643-53.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837-53.
- Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35):
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- Fong DS, Ferris FL, 3rd, Davis MD, Chew EY. Causes of severe visual loss in the early treatment diabetic retinopathy study: ETDRS report no. 24. Early
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- Buse JB, Bigger JT, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99: 21i-33i.
- Accord Study Group, Accord Eye Study Group, Chew EY, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363: 233-44.
- ACCORD Follow-On Eye Study Group. Persistent Effects of Intensive Glycemic Control on Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-On Study. Diabetes Care 2016; 39: 1089-100.