SECTION 6: MANAGEMENT OF DIABETES AND RETINOPATHY 6.1 INTRODUCTION Visual impairment is the most feared long-term consequence of diabetes. Several conditions contribute to the problem of loss of vision in diabetes, including diabetic and hypertensive retinopathy, and increased risks of retinal vascular occlusion, cataract formation and glaucoma. The rise in number of people with diabetes to an estimate of 4 million in UK by 2025, together with increasing life expectancy, are daunting prospects if retinopathy prevalence remains at 40%. However, some optimism is warranted as reversal of retinopathy is possible in the earlier stages and there is evidence from several studies that both proliferative retinopathy and/or severe visual loss have been reduced in recent years. For example in a metanalysis of reports on Type 1 diabetes progression to proliferative retinopathy and severe visual loss was reduced by approximately two-thirds when 1975-85 was compared with 1986- 20081 (level 2). New therapies such as intravitreal treatments may also affect outcome. As management of diabetes and retinopathy improves, other ocular problems may become more dominant as causes of visual loss in diabetes2 . 6.2 RISK FACTORS Risk factors for diabetic retinopathy · Non-modifiable: Genetic factors, gender and duration of diabetes · Modifiable: Glycaemia, blood pressure and lipid levels · Additional factors: Carotid arterial disease, pregnancy, renal impairment and smoking 6.2.1 Glycaemia Level of control The Diabetes Control and Complications Trial (DCCT)3 studying known Type 1 diabetes and the UK Prospective Diabetes Study (UKPDS)4-6 involving newly diagnosed type 2 diabetes have provided good evidence on the importance of glycaemic control on the development of retinopathy and its progression (level 1). After a mean duration of follow-up of 6.5 years DCCT intensive therapy achieved a reduction in mean HbA1c from 76 mmol/mol (9.1%) to 56 mmol/mol (7.3%) with significant reduction in progression of retinopathy (3-step increase on the ETDRS scale) by 76% in the primary prevention group and by 54% in the secondary intervention cohort (Level 1). Importantly no glycaemic threshold was identified at which the risk of retinopathy was eliminated and benefits were seen at all levels of HbA1c. After a mean duration of follow-up of 10 years in the UK Prospective Study reduction of HbA1c from 63 mmol/mol (7.9%) to 53 mmol/mol (7.0%) was associated with a 25% risk reduction of microvascular complications (Level 1). 43 Further confirmation of the value of good glycaemic control in type 2 diabetes was obtained in the ACCORD Eye study where reduction of HbA1c from mean 58 to 46 mmol/mol was associated with reduced primary outcome (3-step increase on the ETDRS scale or development of proliferative retinopathy requiring photocoagulation or vitrectomy) from 10.2% to 6.5% and progression of retinopathy was reduced by 42%7 (Level 1). Metabolic memory and legacy effects Importantly, the idea of metabolic memory or legacy effect of good glycaemic control on retinopathy has been demonstrated by both the DCCT study and UKPDS. In the DCCT/EDIC8 after ten years follow-up where the glycated haemoglobin levels had converged completely, the former intensive treatment group still had 24% reduction in progression of retinopathy and 59% reduction in proliferative retinopathy but the risk reductions at ten years were attenuated compared with the first four years of follow-up. In UKPDS despite glycated haemoglobin differences being lost after the first year in the sulfonylurea–insulin treatment group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and for microvascular disease (24%, P=0.001)9 .(Level 1) Risks of diabetes therapy (tight glycaemic control and thiazolidinediones) Some risk is associated with very tight glycaemic control, not from an ophthalmic point of view, but from increased risk of hypoglycaemia and its possible association with cardiovascular events. In the ACCORD study hypoglycaemia requiring third party assistance was increased from 3.5% to 10.5% (p<0.001) and there was an increased rate of death from any cause (4.0% vs. 5.0%) (Level 1). The main glycaemia trial was therefore stopped early after a mean 3.5 years follow-up, potentially underestimating the reported effect of glycaemia treatment on diabetic retinopathy. It was of interest that it was the median times from the onset of severe hypoglycaemia to the first major macrovascular event, the first major microvascular event and death that were significantly different in the intensively treated group, with no relationship being found between repeated episodes of severe hypoglycaemia and vascular outcomes and death (Level 1). Thiazolidinediones were widely prescribed in the ACCORD study (92% in the intensive therapy group vs. 58% in the standard therapy group) and there have been concerns that rosiglitazone, now withdrawn, was not cardioprotective. Similar findings were noted in the ADVANCE study10 of intensive glycaemic therapy in type 2 diabetes based on sulphonylureas with less than 20% use of thiazolidinediones in which a mean glycated haemoglobin level of 48mmol/mol (6.5%) was achieved in the intensive-control group compared with 56 mmol/mol (7.3%) in the standard-control group. Severe hypoglycaemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P><0.001). The incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control) was reduced. However owing to the possible 2.6-fold increase in macula oedema associated with the use of thiazolidinediones, but not with other anti-diabetic drugs11 (Level 1), current advice is to withdraw pioglitazone when macula oedema has developed. (Level A) 44 Summary · It is recognised that the benefit of good glycaemic control may be seen at any stage in the development of retinopathy – for preventing retinopathy, for regression in the early stages of retinopathy and for reducing the progression to proliferative retinopathy and to severe visual loss. (Level A) · Good glycaemic control early in the course of diabetes has an important impact on long-term outcome of retinopathy. (Level A) Recommendations for management of glycaemia i. A personalised HbA1c target should be set, usually between 48-58 mmol/mol (6.5-7.5%). No threshold level of glycaemia has been shown in any of the larger studies of retinopathy. (Level A) ii. Less strict targets should be set (NICE quality standards June 2011) in patients with established cardiovascular disease and in older subjects. (Level A) iii. Patients should receive an on-going review of treatment to minimise hypoglycaemia. (Level A) iv. Pioglitazone should be avoided in the presence of macula oedema. (Level A/B) 6.2.2 Blood pressure Blood pressure control plays an important role in prevention and management of diabetic retinopathy. The UKPDS showed that a reduction of mean systolic blood pressure from 154 to 144 mmHg reduced microaneurysm count at 4.5 years follow up, reduced hard exudates and cotton-wool spots at 7.5 years, and was aasociated with less need for photocoagulation and less deterioration of 2-step or more on the ETDRS retinopathy scale12. No legacy effect was demonstrated so blood pressure control should be maintained to be effective13. (Level 1) In the ACCORD Eye study7 intensive blood pressure control aiming for systolic blood pressure ><120mmHg was compared with standard control ><140mmHg in the context of good glycaemic control, using all the standard hypotensive medications. The ACCORD Eye study failed to demonstrate a significant effect of intensive blood pressure control on the progression of retinopathy. It is possible that the median systolic pressure of 133mmHg in the non-intensive treatment group was an effective level for preventing progression or that the duration of follow-up was insufficient. (Level 1) A role for angiotensin as an angiogenic growth factor has been suggested. Specific therapies blocking the renin-angiotensin system (RAS) therefore may have additional benefits particularly for mild retinopathy. An early trial using the ACE inhibitor lisinopril was tested over 2 years of follow-up in the EUCLID) study 14(Level 1). This study demonstrated that patients with type 1 diabetes treated with an ACE inhibitor had a significant reduction of 50% in the progression of DR (p=0.02), but the findings were weakened owing to differences in initial and final HbA1C levels favouring lisinopril. The more recent Diabetic Retinopathy Candesartan Trials (DIRECT) programme assessed the effect of treatment of oral candesartan 32 mg daily, an 45 angiotensin-receptor blocker (ARB), on the incidence and progression of diabetic retinopathy. The programme enrolled over 5,000 patients in three arms of the trial, DIRECT-Prevent 1 and -Protect 1in type 1 diabetes15, and DIRECT-Protect 216 in type 2 diabetes (which included treated hypertensive patients), to examine the incidence and progression of diabetic retinopathy over a 5-year period. The primary endpoints for all three arms of the trial were two-step progression of DR or the de novo development of retinopathy in Prevent 1, and no statistically significant changes in these primary endpoints were shown (Level 1). In patients with Type 1 diabetes, candesartan had a borderline effect on reducing the incidence of retinopathy by two or more steps in severity by 18%, but had no effect on progression of retinopathy (Level 1). In post hoc analyses, the incidence of DR of three steps (EDTRS scale) was significantly reduced by 35%. In patients with type 2 diabetes (Protect 2), candesartan treatment resulted in a significant increase in regression of DR by 35% (Level 1). However, an overall significant change towards less severe DR in all three trials was observed (p=0.03–0.003). It is more likely that these effects were specific to RAS blockade rather than an effect of lower blood pressure as baseline blood pressure were 116-117/72-74 in the type 1 diabetes studies and 123-139/75-80 in the type 2 diabetes study with very small changes on treatment. It is reasonable to conclude that RAS blockade in general and candesartan specifically have a place in the medical management of diabetic retinopathy, to prevent the problem in Type 1 diabetes and to treat the early stages in Type 2 diabetes17 . Guidelines for hypertension in diabetes · Intensify therapy aiming for systolic ≤130mmHg in those with established retinopathy and/or nephropathy (Level A). · Encourage regular monitoring of blood pressure in a health care setting and at home if possible. · Recognise that lower pressures may be beneficial overall but evidence is lacking for retinopathy. (Level B) · Recognise that specific therapies blocking the renin-angiotensin system (RAS) may have additional benefits, particularly for mild retinopathy, but should be discontinued during pregnancy. (Level B) · Establish a personalised mean systolic blood pressure target in all patients who do not have retinopathy, usually >< 140mmHg (Level A). 6.2.3 Lipids Lipid-lowering is another approach that may reduce the risk of progression of diabetic retinopathy, particularly macular oedema and exudation. The possibility of an effect of statins has been investigated over the last 10 years with some encouraging results. For example 2838 patients in CARDS followed over a median follow-up of 3.9 years with atorvastatin 10mg daily, showed a trend to reduced laser therapy but no influence on diabetic retinopathy progression18,19(Level 1). Better evidence on the effects of larger doses of statins with longer follow-up is required but, if statins modify retinopathy, the effect is likely to be small. Two large randomised controlled trials of fenofibrate have subsequently confirmed benefit in established retinopathy. Firstly, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study20, fenofibrate ( 200 mg formulation /day) reduced the requirements for laser therapy (both macula and pan retinal/scatter laser) 46 and prevented disease progression in patients with pre-existing diabetic retinopathy (Level 1). These benefits did not appear to be related to changes in lipid levels as there were no reported clinically relevant differences in mean plasma HDL cholesterol or triglyceride concentrations in those with or without laser treatment. Secondly the ACCORD Eye study 7 showed a 40% reduction in the odds of having progression of retinopathy over four years in patients allocated to fenofibrate (160 mg formulation/day) in combination with a statin, compared to simvastatin alone. This occurred with an increase in HDL-cholesterol and a decrease in the serum triglyceride level in the fenofibrate group, as compared with the placebo group, and being noted in the first year of treatment and maintained. Additionally, in ACCORD eye study the effect of fenofibrate was independent of glycaemia (Level 1). However, no data is available to indicate which features of retinopathy progressed or whether any evidence of