David Levy, MD, FRCP
Non-proliferative diabetic retinopathy
Small, red, intraretinal lesions usually found at the posterior pole of the eye, around the disc and macula. They occur in areas of capillary non-perfusion and show leakage of fluorescein. It is worthwhile estimating the number of microaneurysms as it has some prognostic significance; the more there are, the greater the risk of progression to proliferative retinopathy. On their own they do not reduce visual acuity unless at the macula, where even a very small number can significantly affect vision….
Waxy yellow dots or plaques formed by extravasated plasma proteins. Like microaneurysms, they occur early in the course of retinopathy, and affect vision only if they form at the macula.
These are caused by ruptured capillaries situated deeper in the retina than those causing microaneurysms. They can occur in non-diabetic conditions (e.g. anemia, leukemia or hypertension) unrelated to diabetes. There are different types, not always clearly distinguished, and several forms may occur in the same retina:
- dot and blot;
- flame-shaped hemorrhages in the retinal nerve fibre layer, which often look striated, are common in non-diabetic hypertension and sometimes also occur transiently in well-controlled type 1 diabetes;
- deeper hemorrhages with irregular outlines;
- large, dark, ‘cluster’ hemorrhages.
Cotton-wool spots (soft exudates)
These white fluffy-edged lesions, unlike the waxy, more yellow hard exudates, represent accumulation of axoplasmic material adjacent to a retinal infarct. An occasional cotton-wool spot is of little significance, but in greater numbers (> 5) they may indicate rapidly advancing retinopathy, associated hypertension, or unrelated conditions (e.g. vasculitis).
Multiple soft exudates frequently accompany pre-proliferative retinopathy, though this view has been challenged. Distinguish between soft exudates and soft drusen, associated with progression to AMD: drusen occur only at the macula, and symmetrically in both eyes.
Patients with either no retinopathy or with NPDR but no maculopathy are invited for rescreening in England every year. No ophthalmological treatment is required for NPDR, but 6-monthly examination may be valuable in patients with multiple lesions of background retinopathy (sometimes aptly described as ‘active’ retinopathy), especially if there is poor control of glucose and blood pressure, as there is a risk of rapid progression. In addition, there are several important practical points relating to diabetes management and background retinopathy.
Management of background retinopathy (Box 9.2)
Maintaining HbA1c at 7% (53 mmol/mol) in the DCCT reduced the rate of progression in those with background changes at baseline (about 10% progression at HbA1c 7%, and about half that rate at 6%, 42 mmol/mol). Almost identical results were obtained in type 2 diabetes in the intensive intervention group in UKPDS. More recent studies have not given consistent messages: neither VADT nor ADVANCE (including a detailed retinal substudy, AdRem ) found intensive glycemic control to improve any measure of retinopathy, but ACCORD Eye showed a substantial effect of very intensive glycemic control (HbA1c ~ 6.5%), though with an attendant risk of hypoglycemia and possible increased overall mortality . Taking the results of UKPDS and ACCORD Eye together, patients with retinopathy should aim for HbA1c levels between 6.5 and 7.0%, though it is still not clear whether maculopathy responds in the same way.
DCCT/EDIC demonstrated a dramatic ‘legacy’ effect of tight glycemic control on retinopathy in type 1 diabetes; the benefits outlasted the relaxation of intensive control by at least 7 years. However, the effect had disappeared by year 10 of EDIC in adolescents who had entered DCCT. Control was worse than in the adults during DCCT (HbA1c 8.9%, 74 mmol/mol vs. 8.1%, 65 mmol/mol), though there was no difference during EDIC. This finding reinforces the need for the best possible glycemic control from the outset in type 1 diabetes. Intensive multimodal intervention in the Steno-2 study accounts for a similar legacy effect in type 2 diabetes. Even though glycemic control was indifferent, retinopathy progression, laser treatment and blindness were all markedly reduced in the original intensively managed group; Steno-2-like interventions should be mandatory, regardless of the glycemia.
Effect of rapid improvement in glycemic control on retinopathy
Rapidly improving glycemic control can cause sometimes dramatic but transient deterioration in retinopathy. It was first noted in the 1980s in studies of intensive control in type 1 diabetes, and later in DCCT. The mechanism is not known, but retinal ischemia is involved, as the hallmark lesion is cotton-wool spots, which develop within 3–6 months but which usually resolve by 1 year. Laser treatment is occasionally needed, but the eventual visual outcomes are consistently better if good control is maintained. Whenever intensive treatment starts, especially where there is poor baseline glycemic control, close retinal monitoring is important. DCCT suggests 3-monthly monitoring in high-risk groups, for example:
- in the preconception period and early pregnancy;
- in patients starting pump therapy or any intensive therapy when in poor control;
- any patient with known retinopathy where there has been a fall in HbA1c of over 2% (22 mmol/mol), whatever the reason.
The situation in type 2 diabetes, especially the development of macular oedema, is not clear. Massive reductions in HbA1c (e.g. 4–6%, 44–66 mmol/mol) can occur over a short period with any form of intensive intervention, including bariatric surgery (see Chapter 6). In patients with known retinopathy, monitoring every 3–6 months would be wise, but there is no evidence for this approach, and it may be difficult to organize. Glitazone use has been associated with cases of macular oedema, but in large-scale trials does not seem to be overall more common (see Chapter 6).
Blood pressure and angiotensin blocker treatment
As more trials report, evidence for the benefit of intensive blood pressure reduction on retinopathy in type 2 diabetes becomes less clear-cut, perhaps because patients are entering modern clinical trials with better overall control of blood pressure. In the UKPDS, intensive blood pressure control (144/82 from 160/94 mmHg at baseline) over 6–9 years reduced progression of retinopathy and visual deterioration, but maintaining approximately the same levels for 4 years in the ADVANCE trial (baseline 145/81, achieved 138/78 mmHg) had little benefit, and neither did even more intensive control in ACCORD Eye (baseline 139/77, achieved 119/64 mmHg). Nevertheless in microalbuminuric patients, such as those in Steno-2, blood pressure should be maintained at about 130/70 mmHg in order to contribute to lowering the risk of retinopathy.
Specific drugs have been studied. In EUCLID/EURODIAB (1998) the ACE-i lisinopril reduced the risk of retinopathy progression, including progression to proliferative retinopathy in type 1 diabetes, but it was a short study and the treatment groups were unbalanced. In the large DIRECT studies (2008), candesartan 32 mg daily for 5 years slightly reduced the risk of developing new-onset retinopathy, but did not slow progression of pre-existing retinopathy in type 1 diabetes . In type 2 patients with mild-to-moderate retinopathy, the same regimen improved outcomes (modest effect on regression and reducing overall retinopathy) . All patients had negative microalbuminuria (or they would already have been taking angiotensin blockade). Translating these undramatic findings into clinical practice is difficult. In type 1 patients, it would be difficult to justify this length of drug treatment in patients without retinopathy when DCCT showed that good glycemic control would have a greater effect on retinopathy prevention and progression (and would reduce all other complications as well), though it might be justifiable in the chronically poorly controlled. Very few type 2 patients escape angiotensin blockade treatment for other indications.
Aspirin, even at high doses (e.g. 650 mg/day in the ETDRS study in type 1 and 2 patients), does not benefit retinopathy, but it reduces the risk of myocardial infarction. However, it does not increase the risk of retinal hemorrhage. Aspirin use should therefore be based on assessment of cardiovascular risk without regard to retinopathy status (see Chapter 11). There is no evidence for its benefit in type 1 patients with isolated background retinopathy. Atorvastatin may slightly reduce the need for laser treatment in type 2 diabetes (CARDS) but the effect was not statistically significant. Fenofibrate 200 mg daily in the FIELD study (2007) had a more dramatic effect (40% reduction) on the need for laser treatment in mildly dyslipidemic type 2 patients, but it had no long-term effect on the lipid profile in this study, so another mechanism must be responsible. Very interestingly, fenofibrate reduced the risk of significant progression of retinopathy in ACCORD Eye (see Chapter 12) in patients already taking simvastatin; two major trials have now confirmed that fenofibrate reduces the risk of severe retinopathy. Although the mechanism is not clear, there may be now some justification for the use of this agent in patients with progressing retinopathy, where all other risk factors are under control. Patients, especially type 1, must stop smoking, as current smoking is associated with proliferative changes and visual impairment.
- Nathan DM, Zinman B, Cleary PA et al. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 2009;169:1307–16. PMID: 19636033.
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- Chew EY, Ambrosius WT, Davis MD et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. ACCORD Study Group and ACCORD Eye Study Group. N Engl J Med 2010;363:233–44.
- Chaturvedi N, Porta M, Klein R et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008;372:1394–402. PMID: 18823656.
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- Reaven PD, Emanuelle N, Moritz T et al. Proliferative diabetic retinopathy in type 2 patients is related to coronary artery calcium in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 2008;31:952–7. PMID: 18316393.
- Al-Ansari SA, Tennant MT, Freve MD, Hinz BJ, Senior PA. Short report: sub-optimal diabetes care in high-risk diabetic patients attending a specialist retina clinic. Diabetic Med 2009;26:1296–300. PMID: 20002485.
- Shah AS, Chen SH. Cataract surgery and diabetes. Curr Opin Ophthalmol 2010;21:4–9. PMID: 19935423.
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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK
This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)