Abstract
Diabetic maculopathy is a common complication of diabetes mellitus, characterised by macular oedema and frequently accompanied by lipid exudation. It is the major cause of loss of vision from diabetic retinopathy. There is some evidence to implicate serum lipids in exudative maculopathy; cross-sectional studies suggest that higher serum lipid levels are found in patients with macular exudates, and prospective studies have shown an increased risk of exudative maculopathy if baseline cholesterol is higher.
The treatment for diabetic maculopathy is laser photocoagulation of the pigment epithelium. With the advent of systemic lipid lowering therapy over the last decade, there may be potential for medical therapy also. There is some anecdotal evidence of the effect of lipid lowering agents (particularly statins) in reducing exudate, and a number of studies have shown that lipid lowering therapy may reduce macular exudates, but numbers in these trials are small. A randomised controlled trial is now required to investigate whether the use of systemic lipid lowering therapy is of benefit in patients with exudative maculopathy, even in the absence of dyslipidaemia.
Similar content being viewed by others
Introduction
Diabetic retinopathy is a major microvascular complication of diabetes, and is the commonest cause of blindness in people of working age in the Western world. Diabetic maculopathy, defined as retinopathy within one disc diameter of the centre of the macula, is a major cause of sight loss in diabetes.1
Diabetic maculopathy comprises two aspects: (i) retinal oedema in which fluid and lipoproteins accumulate within the retina; and (ii) macular ischaemia in which there is closure of perifoveal capillaries demonstrable on fundus fluorescein angiography. It is not known to what extent macular ischaemia contributes to the visual loss attributable to diabetic maculopathy and in this article we are limiting our discussion to macular oedema.
Macular oedema per se may be difficult to diagnose on fundoscopy, where subtle macular thickening may be responsible for insidious loss of vision. Exudates are easier to see and are a frequent component of retinal capillary leakage (termed exudative maculopathy). They do not affect vision until they encroach into the fovea at which time vision is irretrievably lost.
This article examines the role of serum lipids in exudative maculopathy and discusses the potential for systemic lipid modulation to prevent visual loss.
Epidemiology of maculopathy
The largest population-based survey of diabetic retinopathy is the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR).2 This study examined three groups of patients with diabetes: (i) younger onset insulin-treated (mostly type 1 diabetes); (ii) older onset insulin-treated (mostly type 2); and (iii) older onset not insulin-treated (type 2). The prevalence of maculopathy was consistently higher in older onset insulin-treated patients rising to a peak of 25% at 15 years duration of diabetes. Only 12% of older onset patients with diabetes not on insulin had maculopathy, although it was more commonly associated with lipid exudation in this group. Eighteen per cent of younger onset diabetic patients had maculopathy and in 65% of these it was accompanied by proliferative diabetic retinopathy (PDR).
Similar prevalence data were reported in a large cross-sectional study of maculopathy from a hospital diabetic eye clinic population.3 Fifteen per cent of type 1 and 23% of type 2 patients had maculopathy. However, in this study, maculopathy in type 1 patients was more commonly associated with non-proliferative diabetic retinopathy (NPDR) (42%) than with PDR (42% vs 35%). In type 2 patients, the prevalence was similar in both groups (53% NPDR, 56% PDR). In both groups the numbers with maculopathy increased with duration of diabetes.
The Melton Mowbray study describes a cross-sectional survey of the prevalence of diabetic retinopathy in a cohort of patients with diabetes residing in one town.4 Maculopathy was present in 10% of the diabetic cohort. Risk factors identified for maculopathy in this study included age, female sex, duration of diabetes, cigarette smoking and systolic blood pressure.
Pathogenesis of diabetic maculopathy
The pathogenic mechanisms underlying diabetic retinopathy are not clear. Changes in retinal basement membrane extra-cellular matrix proteins,5 haemodynamic changes,6 growth factors7 and cytokines8 have been implicated.
A number of pathological changes occur in the retinal capillary circulation of the diabetic macula, including microaneurysm formation, capillary dilatation and closure. Macular oedema is thought to be caused principally by breakdown of the inner blood-retinal barrier. Focal oedema results from leakage across retinal microaneurysms, diffuse oedema from leakage by abnormally dilated capillaries, arterioles and venules of the macular circulation. It is postulated also that the outer retinal barrier is abnormal. Tight junctions between retinal pigment epithelial cells (RPE) may be affected by changes in structural proteins such as occludin and ZO-19 and transport across the RPE may be altered.
There is some evidence that vascular endothelial growth factor (VEGF) from retinal cells (eg RPE, pericytes, endothelial cells, Mueller cells, astrocytes) may be implicated in this deterioration of the blood-retinal barrier.10 The link between the systemic abnormalities of diabetes and changes in the blood retinal barrier is poorly understood.
Are serum lipids associated with increased risk of maculopathy?
There has been considerable study of the risk factors for the development of diabetic retinopathy. In both type 1 and type 2 diabetic subjects, duration of diabetes,3 glycaemic control,11,12 presence of hypertension and nephropathy13 have been associated with increased risk of retinopathy. There has been interest in the link between serum lipids and retinal exudates for 40 years.14 A number of cross-sectional studies suggest that serum lipids may have a causative role in the development of macular exudates. Comparison of a small group of diabetic patients with severe exudative maculopathy to a group with non-exudative retinopathy demonstrated a significantly higher level of serum triglyceride in the former group, although serum cholesterol was not significantly different.15 A case control study (n = 26) where patients were matched for age, gender, glycaemic control, duration and treatment of diabetes, found a trend for patients with maculopathy to have higher serum lipids over 7 years’ follow-up than patients without.16 An elevation in cholesterol has been shown in studies of exudative maculopathy in type 1 diabetes.17 Further studies have linked LDL cholesterol with maculopathy, although numbers of patients in these studies are small.18,19 A direct toxic effect of LDL on retinal capillary pericytes has also been demonstrated, and this toxic effect can be enhanced by LDL glycation or oxidation. In other small cross-sectional studies, lipoprotein (a) has been suggested as a risk factor for maculopathy,20,21 although this finding is refuted on examination of a small subset of the WESDR population.22 Improved outcome following laser photocoagulation therapy for macular oedema has been reported in subjects who have higher HDL cholesterol or normal total cholesterol.23
The role of dietary fat intake and its influence on exudative maculopathy has been examined. In 1965, Ernst reported reduction in retinal exudates in eight diabetic patients after 2–3 years of a carbohydrate-rich, fat-poor diet.24 Seven year follow-up of a cohort of 149 patients randomised to a low carbohydrate or modified fat diet (rich in polyunsaturated fats) showed that patients with low levels of linoleic acid in cholesterol ester had greater risk of retinopathy.25
Stronger evidence for a role of serum lipids in exudative maculopathy is suggested in prospective studies. In the Early Treatment Diabetic Retinopathy Study (ETDRS),26 a subgroup of 2709 of the original 3711 patients had serum lipids measured. Higher baseline total and LDL cholesterol levels increased the risk of retinal exudation by two-fold at baseline. Patients with higher baseline total cholesterol, LDL cholesterol or triglycerides, had a greater risk of developing maculopathy during the course of the study. On multivariate analysis, risk of losing visual acuity was associated with severity of hard exudation, even after adjusting for macular oedema. In further analyses, elevated serum cholesterol at baseline increased the risk of visual loss by 50% compared to lower serum cholesterol levels. These findings have been supported by examination of a subgroup of the WESDR cohort.27 Increased total cholesterol was noted in patients with increased severity of retinopathy and hard exudate.
One recent study of Age-related Macular Degeneration (AMD) suggests that statin therapy does have a protective role against the development of AMD.28 In this cross-sectional survey, it was noted that statin use was associated with less AMD, possibly due to reductions in basal linear deposits in Bruch membrane or anti-oxidant effects.
These studies all suggest a causal link between exudative maculopathy in diabetic subjects, and their prevailing lipid profile.
Therapy to improve diabetic maculopathy
The established treatment for exudative diabetic maculopathy is laser photocoagulation, which is sight preserving.29,30,31 More recently, surgical therapy, such as pars planar vitrectomy, has been advocated.32 A number of other therapies have been suggested as effective particularly in severe exudation. Loss of negatively charged proteoglycans such as heparan sulphate from the retinal basement membrane has been suggested as leading to increased vascular permeability.33 It was this observation that has led to a trial of danaparoid sodium, a proteoglycan molecule, in patients with diabetic nephropathy.34 On retrospective review of these patients, it was noted that significant improvement in macular hard exudates occurred during 6 weeks of therapy with danaparoid sodium.35 This small study has yet to be reproduced in a large randomised trial. More recently, calcium dobesilate has been suggested as reducing vascular leakage in diabetic retinopathy by reducing microvascular permeability and also having an anti-oxidant effect.36 A small randomised trial of the drug, however, has not demonstrated any beneficial effect on reducing progression of retinopathy.37 Anecdotally, treatment of renal failure associated anaemia with erythropoietin has also resulted in improvement in hard exudation,38 as has heparin-induced extra-corporeal dialysis.39
Lipid lowering therapy in exudative maculopathy
Statin therapy has been proven to reduce cardiovascular events in patients with dyslipidaemia, both in the primary,40 and secondary41 prevention settings. More recently, fibrate therapy has also demonstrated reduction in cardiovascular events in patients with low HDL and high triglyceride levels post myocardial infarct.42 These drugs are thus proven to reduce cardiovascular disease in the presence of dyslipidaemia.
Interestingly, these trials of lipid lowering therapy in diabetic maculopathy were undertaken before any significant evidence of a role for lipids in maculopathy was available. These small trials of either clofibrate or atromid in exudative maculopathy have suggested that a reduction in macular hard exudates could be achieved, but with little improvement in visual acuity.43,44 Of note, however, is that the visual acuity of the patients in these trials was poor at the outset, and hence a significant improvement with lipid lowering therapy may not be expected. A more recent German pilot study used etofibrate in patients with type 2 diabetes and type 2b hyperlipoproteinaemia with diabetic maculopathy.45 Clear regression of macular exudates was seen in seven of 10 patients in 6 months. Two small pilot studies have used statin therapy in diabetic retinopathy.46,47 In one pilot study, six patients with exudative maculopathy were treated with pravastatin, which lowered their total and LDL cholesterol by 40%. Over one year, an improvement in hard exudates in all six patients, with reduced microaneurysms in four patients was observed, and acuity improved in one patient.
Conclusions and further studies
Lipid exudation at the diabetic macula is the result of increased vascular permeability, plus a dysfunctional outer blood-retina barrier and retinal pigment epithelium. There is now compelling evidence that serum lipoproteins have a major role in exudative maculopathy in patients with diabetes, such that increasing total or LDL cholesterol is accepted as a risk factor for maculopathy.
Type 2 diabetes is characterised by hyperglycaemia. It is now widely recognised that disordered lipid metabolism and a tendency to angiopathy are also major characteristics of diabetes. Recent advances in lipid lowering therapy have presented us with the opportunity to intervene effectively in dyslipidaemia with the use of either statins or newer fibrates. Whilst primary prevention studies on macrovascular disease specifically in diabetic patients are ongoing, the recently published Joint British Societies guidelines suggest that lipid lowering therapy should be instituted on the basis of Coronary Heart Disease Risk, calculated using the Framingham Equation.48
The presence of exudative maculopathy is not currently an indication for institution of lipid lowering therapy. It is not known whether exudative maculopathy may improve with the use of a statin or a fibrate, even in the absence of significant dyslipidaemia, and whether this improvement leads to improved visual outcome. One study of fenofibrate in patients with diabetes has included retinal photography, and hence may contribute to the debate. It is clear, however, that a randomised controlled trial of lipid lowering therapy in patients with exudative maculopathy is required to answer these questions.
The St Vincent declaration some 10 years ago set out a reduction in visual loss of 30% as a major aim of diabetes care over the coming decade.49 Whilst improving anti-hyperglycaemic and anti-hypertensive therapy is likely to reduce the incidence of maculopathy, reducing the progression of exudative maculopathy to marked visual loss must be also considered a priority, and lipid lowering therapy has the potential to augment laser photocoagulation in reducing visual loss in exudative maculopathy.
References
Henricsson M, Tyrberg M, Heijl A, Janson L . Incidence of blindness and visual impairment in diabetic patients participating in an ophthalmological control and screening programme. Acta Ophthalmol Scan 1996; 74: 533–538
Klein R, Davis MD, Moss SE, DeMets DL . The Wisconsin Epidemiologic Study of Diabetic Retinopathy. A comparison of retinopathy in younger and older onset diabetic persons. Adv Exp Med Biol 1985; 189: 321–335
Zander E, Herfurth S, Bohl B, Heinke P, Herrmann U, Kohnert K et al. Maculopathy in patients with diabetes mellitus type 1 and type 2: associations with risk factors. Br J Ophthalmol 2000; 84: 871–876
Sparrow JM, McLeod BK, Smith TD, Birch MK, Rosethal AR . The prevalence of diabetic retinopathy and maculopathy and their risk factors in the non-insulin treated diabetic patients of an English town. Eye 1993; 7: 158–163
Roberts JM, Forrester JV . Factors affecting the migration and growth of endothelial cells from microvessels of bovine retinae. Exp Eye Res 1990; 50: 165–172
Kohner EM, Patel V, Rassam SBM . Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes 1995; 44: 603–607
Forrester JV, Shafiee AF, Schroder S, Knott R, McIntosh L . The role of growth factors in proliferative retinopathy. Eye 1993; 7: 276–287
Abu el Asrar AM, Maimone D, Morse PH, Gregory S, Reder AT . Cytokines in the vitreous of patients with proliferative diabetic retinopathy. Am J Ophthalmol 1992; 114: 731–736
Antcliff RJ, Marshall J . The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol 1999; 14: 223–232
Murata T, Ishibashi T, Khalil A . Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Research 1995; 27: 48–52
Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med 1993; 329: 977–986
United Kingdom Prospective Diabetes Study 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: 837–853
United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–713
Esmann V, Lundbaek K, Madsen PH . Types of exudates in diabetic retinopathy. Acta Medica Scandinavica 1963; 174: 375–384
Brown GC, Ridley M, Haas D, Lucier AC, Sarin LK . Lipaemic diabetic retinopathy. Ophthalomology 1984; 91: 1490–1495
Dodson PM, Gibson JM . Long term follow-up of and underlying medical conditions in patients with diabetic exudative maculopathy. Eye 1991; 5: 699–703
Miccoli R, Odello G, Giampietro O, Marchetti P, Cristofani R, Penno G et al. Circulating lipid levels and severity of diabetic retinopathy in type 1 diabetes mellitus. Ophthalmic Res 1987; 19: 52–56
Mohan R, Mohan V, Susheela L, Ramachandran A, Viswanathan M . Increased LDL cholesterol in non-insulin dependent diabetics with maculopathy. Acta Diabetol Lat 1984; 21: 85–89
Dornan TL, Carter RD, Bron AJ, Turner RC, Mann JI . Low density lipoprotein cholesterol: an association with the severity of diabetic retinopathy. Diabetologia 1982; 22: 167–170
Guerci B, Meyer L, Sommer S, George JL, Ziegler O, Drouin P et al. Severity of diabetic retinopathy is linked to lipoprotein (a) in type 1 diabetes. Diabetes Metab 1999; 25: 412–418
Kim CH, Park HJ, Park JY, Hong SK, Yoon YH, Lee KU . High serum lipoprotein (a) levels in Korean type 2 diabetic patients with proliferative diabetic retinopathy. Diabetes Care 1998; 21: 2149–2151
Haffner SM, Klein BE, Moss SE, Klein R . Lp(a) is not related to retinopathy in diabetic subjects. Eur J Ophthalmol 1995; 5: 119–123
Kremser BG, Falk M, Kieselbach GF . Influence of serum lipid fractions on the course of diabetic macular edema after photocoagulation. Ophthalmologica 1995; 209: 60–63
Ernst I, Linner E, Svanborg A . Carbohydrate-rich, fat-poor diet in diabetes. Am J Med 1965; 39: 594–600
Dowd TC, Howard-Williams J, Thursfield V, Bron AJ, Hockaday TM, Mann JI . Diabetic retinopathy: different risk factors for exudates and haemorrhages. Int Ophthalmol 1986; 9: 11–15
Chew EY, Klein ML, Ferris FL, Remaley NA, Murphy RP, Chantry K et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) report 22. Arch Ophthalmol 1996; 114: 1079–1084
Klein BE, Moss SE, Klein R, Surawicz TS . The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XIII. Relationship of serum cholesterol to retinopathy and hard exudate. Ophthalmology 1991; 98: 1261–1265
Hall NF, Gale CR, Sydall H, Phillips DIW, Martyn CN . Risk of macular degeneration in users of statins: cross sectional study. BMJ 2001; 323: 375–376
Stefaniotou M, Kalogeropoulos C, Psilas K . Long-term visual results after laser photocoagulation for diabetic maculopathy. Ophthalmologica 1995; 209: 64–67
Davies EG, Petty RG, Kohner EM . Long term effectiveness of photocoagulation for diabetic maculopathy. Eye 1989; 3: 764–767
Anonymous. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Early Treatment Diabetic Retinopathy Study Research Group. Arch Opthalmol 1995; 113: 1144–1155
Yang CM . Surgical treatment for severe diabetic macular edema with massive hard exudates. Retina 2000; 20: 121–125
Deckert T, Feldt Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A . Albuminuria reflects widespread vascular damage. The Steno Hypothesis. Diabetologia 1989; 32: 219–226
Myrup B, Hansen PM, Jensen T, Kofoed-Enevoldsen A, Feldt-Rasmussen B, Gram J et al. Effect of low-dose heparin on urinary albumin excretion in insulin-dependent diabetes mellitus. Lancet 1995; 345: 421–422
van der Pijl JW, van der Woude FJ, Swart W, van Es LA, Lemkes HHPJ . Effect of danaparoid sodium on hard exudates in diabetic retinopathy. Lancet 1997; 350: 1743–1745
Berthet P, Farine JC, Barras JP . Calcium dobesilate: pharmacological profile related to its use in diabetic retinopathy. Int J Clin Pract 1999; 53: 631–636
Haas A, Trummer G, Eckhardt M, Schmut O, Uygumer I, Pfeiffer KP . Effect of calcium dobesilate on progression of diabetic retinopathy. Klin Monatsbl Augenheilkd 1995; 207: 17–21
Berman DH, Friedman EA . Partial absorption of hard exudates in patients with diabetic end stage renal disease and severe anaemia after treatment with erythropoietin. Retina 1994; 14: 1–5
Janknecht P, Schumann M, Hansen LL . Reduction of retinal exudates in diabetic retinopathy after heparin-induced extracorporeal LDL-precipitation (HELP). A case report. Eur J Ophthalmol 1996; 6: 340–342
The West of Scotland Coronary Prevention Programme Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. N Engl J Med 1995; 333: 1301–1307
The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–1389
Rubins H, Robins SJ, Collins D, Fye C, Anderson JW, Elam MB et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high density lipoprotein cholesterol. N Engl J Med 1998; 341: 410–418
Duncan LJ, Cullen JF, Ireland JT, Nolan J, Clarke BF, Oliver MF . A three year trial of atromid therapy in exudative diabetic retinopathy. Diabetes 1968; 17: 458–467
Cullen JF, Ireland JT, Oliver MF . A controlled trial of Atromid therapy in exudative diabetic retinopathy. Trans Ophthalmol Soc UK 1964; 84: 281–295
Freybarger H, Schifferdecker E, Schatz H . Regression of hard exudates in diabetic background retinopathy in therapy with etofibrate antilipaemic agent. Med Klin 1994; 89: 594–597
Gordon B, Chang S, Kavanagh M, Berrocal M, Yannuzzi L, Robertson C et al. The effect of lipid lowering on diabetic retinopathy. Am J Ophthalmol 1991; 112: 385–391
Dale J, Farmer J, Jones AF, Gibson JM, Dodson PM . Diabetic ischaemic and exudative maculopathy: are their risk factors different?. Diab Med 2000; 17: 47
Wood D, Durrington P, Poulter N, McInnes G, Rees A, Wray R . Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80 (Suppl 2): S1–S29
St Vincent Study Group. Diabetes Care and Research in Europe: the St Vincent Declaration. Diab Med 1990; 7: 360
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chowdhury, T., Hopkins, D., Dodson, P. et al. The role of serum lipids in exudative diabetic maculopathy: is there a place for lipid lowering therapy?. Eye 16, 689–693 (2002). https://doi.org/10.1038/sj.eye.6700205
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.eye.6700205
Keywords
This article is cited by
-
External limiting membrane: retinal structural barrier in diabetic macular edema
International Journal of Retina and Vitreous (2021)
-
Serum vascular endothelial growth factor is a biomolecular biomarker of severity of diabetic retinopathy
International Journal of Retina and Vitreous (2019)
-
‘Statins in retinal disease’
Eye (2018)
-
Enhancement of scutellarin oral delivery efficacy by vitamin B12-modified amphiphilic chitosan derivatives to treat type II diabetes induced-retinopathy
Journal of Nanobiotechnology (2017)
-
PPARα: an emerging therapeutic target in diabetic microvascular damage
Nature Reviews Endocrinology (2010)