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Epidemiology of diabetic eye disease
Chapter 4
Epidemiology of diabetic eye disease Gillian C. Vafidis
Introduction Diabetic eye disease is an important cause of world blindness (Ghafour et al., 1983; National Society to Prevent Blindness, 1993). The study of its epidemiology improves our understanding of diabetic eye disease and suggests ways in which visual loss may be prevented. The first report of retinal problems in diabetes was by Von Jaeger in Vienna in 1856. Since that time there have been a number of epidemiological studies concerned with dia-
betic-related eye problems (Stolk et al., 1995; Framingham Eye Study, 1980; Houston, 1982; Foulds et al., 1983), the most comprehensive being The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), which has reported on over 2300 diabetic inhabitants of Southern Wisconsin, United States (USA) over the last 14 years (Klein et al., 1984a). The findings of this study provide much of the statistical data discussed in this chapter. Table 4.1 defines the epidemiological terms used.
Table 4.1 Definition of epidemiological terms Term
Definition
Epidemiology
The study of patterns of diseases within populations
Prevalence
The number of cases in a given population at a single point in time
Incidence
The number of new cases in a specified population over a specified time period
Type 1 diabetes
Diabetes diagnosed before the age of 30 years, controlled by insulin injections
Type 2 diabetes
Diabetes diagnosed at or after the age of 30 years, controlled by insulin injection, hypoglycaemic medication or diet alone
Risk factors
Factors that increase the chances of an individual or population developing a specified disease or complication
Relative risk
An assessment of the influence of a risk factor on the rate (or risk) of an event occurring. It measures the strength of an association between a risk factor and disease, but cannot prove a causal relationship between the risk factor and disease
Odds ratio
An approximation to relative risk. It compares the risk of disease in someone with a given risk factor to that in someone without
Epidemiology of diabetic eye disease
Epidemiology of blindness in diabetes Diabetes is the leading cause of blindness in the working population in developed countries. It accounts for 7–8 per cent of all blind registrations and for 1000 new blindness registrations in the UK each year (Evans, 1995), most of which are for diabetic retinopathy. It is the single most important cause of preventable blindness, and it has been estimated that individuals with diabetes have a 25 times higher risk of going blind than those without the disease (Kahn and Hiller, 1974). Diabetic retinopathy causes blindness in one of two ways, either by direct involvement of the macular capillaries or from the complications of proliferative disease. In young patients, where diabetes is diagnosed before the age of 30 years (Type 1 diabetes), blindness is usually as a consequence of proliferative disease. In people diagnosed after the age of 30 years (Type 2 disease), visual impairment is most frequently due to cataract and blindness from diabetic macular oedema (Klein et al., 1984b). Type 2 disease is associated with the highest incidence of blindness, with 4 per cent of those using insulin and 4.8 per cent of those not using insulin going blind over a 10-year period (Klein et al., 1994a). Cataract is the major cause of blindness in the developing world (Wilson, 1980). Where malnutrition is common diabetes is uncommon, but as life expectancy and standards of living rise it is anticipated that diabetes and consequently diabetic retinopathy will become a major cause of blindness in the developing world.
Prevalence of diabetic eye disease Diabetes is estimated to affect 100 million people world-wide. In western countries the prevalence is between 2 and 4 per cent of the population. The majority have ‘maturity onset’ Type 2 disease, and only 10–15 per cent have Type 1 diabetes, i.e. they developed the disease in childhood or in young adult life. The age at onset determines the frequency and nature of diabetic eye complications.
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The major ocular complication of diabetes is retinopathy, which is present in one-third of all individuals with diabetes. Younger onset patients have the highest prevalence and the most severe retinopathy. Less frequent and less severe diabetic retinopathy is found in older onset patients not using insulin (Kahn and Hiller, 1974). The ocular consequences of diabetes are not confined to retinopathy, and include cataract and cranial nerve palsies. Significant cataract was found in 60 per cent of the diabetic population aged 30–54 years in the WESDR (Klein et al., 1985), a five-fold increased prevalence over that of a control population. Intraocular inflammation, glaucoma and retinal vascular disease are also more commonly found in diabetic patients than in a nondiabetic population.
Diabetic retinopathy Prevalence of diabetic retinopathy Diabetic retinopathy principally affects small retinal blood vessels. Its onset and development are related to a number of factors: the type and control of diabetes, concurrent circulatory, hormonal and metabolic problems, and the race, age, sex and diet of the individual. For both Type 1 and Type 2 diabetes, a consistent predictor of the presence of retinopathy is the duration of the systemic disease. The longer an individual has had diabetes, the more likely is diabetic retinopathy. After 5 years of diabetes, the overall prevalence of any retinopathy is 25 per cent. After 10 years this figure has risen to 60 per cent, and by 15 years 80 per cent of all diabetic individuals will have retinopathy. Type 1 patients demonstrate the strongest relationship between diabetic retinopathy and duration of disease (Palmberg et al., 1981). At diagnosis of Type 1 disease retinopathy is unusual, but by 15 years of diabetes, it is an almost universal finding. A similar association with disease duration occurs in Type 2 diabetes, although significant retinopathy is already present at diagnosis in up to 30 per cent
46
Diabetic Eye Disease
Figure 4.1 Prevalence of diabetic retinopathy with type and duration of disease. The frequency of retinopathy at diagnosis is higher in Type 2 disease. The frequency of retinopathy in Type 1 disease is almost 100 per cent after 15 years’ duration. Data from WESDR (Klein et al., 1984a, 1984c).
Figure 4.2 Ten-year incidence and progression of retinopathy with type of diabetes. The incidence of new retinopathy, the progression of existing retinopathy and the incidence of proliferative retinopathy are higher in patients using insulin. Data from WESDR (Klein et al., 1994).
and the frequency of retinopathy never reaches the high prevalence levels of Type 1 disease, even after 25 years (Klein et al., 1984c) (Figure 4.1)
retinopathy at the start developed it over a 4-year period. Significant progression of retinopathy also occurred in this group. One in ten of those with non-proliferative disease progressed to proliferative retinopathy within 4 years (Klein et al., 1989a). In people with Type 2 disease using insulin who did not have any retinopathy at the start of the study, nearly 50 per cent developed new retinopathy and 7 per cent developed proliferative disease after 4 years. Even in Type 2 diabetes controlled on hypoglycaemic medication and/or diet, a third developed new retinopathy and a quarter had progression of existing retinopathy (Klein et al., 1989b). The 10-year incidence and progression of retinopathy is shown in Figure 4.2.
Incidence of retinopathy The incidence of retinopathy is an index of the development of new or progressive retinal disease occurring within a diabetic population in a specified period of time. Incidence data are especially useful for planning health resources. It is important to be able to estimate the number of people within a population who are likely to develop sight-threatening disease over a given time interval so that appropriate health provision can be planned. The Wisconsin Study looked at the number of new cases of retinopathy in the study population, and also at progression of retinopathy in those with pathology at the start of the study. When comparing Type 1 with Type 2 diabetes, they found that the highest incidence of new retinopathy was in Type 1 patients. Nearly 60 per cent of Type 1 patients without
Risk factors In a given individual, the risk of diabetes is a function of genetic inheritance, age, obesity, level of physical activity, cigarette smoking and alcohol use. Risk factors for diabetic retinopathy have also been identified. These factors
Epidemiology of diabetic eye disease
47
Table 4.2 Known risk factors for the development and progression of diabetic retinopathy Type 1 (age at onset less than 30 years)
Type 2 (age at onset over 30 years)
Higher blood sugar levels Higher diastolic blood pressure Gross proteinuria Increased age Male sex
Higher blood sugar levels Higher systolic blood pressure Presence of proteinuria Use of insulin
influence the type and progression of disease, and offer the hope that by their manipulation the onset of retinopathy may be delayed or prevented altogether. Genetic risk factors Genetic risk factors are important in both Type 1 and Type 2 diabetes. Specific chromosomal patterns appear to correspond to the development of diabetic retinopathy in Type 1 diabetes. For example, the presence of HLA-B15 histocompatibility antigen increases four-fold the risk of developing retinopathy. Identical twin studies in Type 2 diabetes have shown that equivalent grades of retinopathy in sibling pairs occur significantly more often than can be attributed to chance alone (Barnett et al., 1981). Blood sugar control Metabolic risk factors are highly significant in the development and progression of diabetic retinopathy. Table 4.2 lists the risk factors for the development and progression of retinopathy. Uncontrolled blood sugar is the most important determinant of the development and progression of diabetic retinopathy so far identified. A large trial in the USA, the Diabetes Control and Complications Trial (DCCT, 1993), found that strict control of blood sugar in Type 1 diabetes reduced the 5-year risk of new retinopathy by 76 per cent and the risk of progression of existing retinopathy by 54 per cent. In Type 2 disease, uncontrolled hyperglycaemia is also recognized to be a risk factor for retinopathy. Data from the WESDR shows the association of 10-year incidence of retinopathy with blood sugar control
at baseline for both Type 1 and Type 2 patients (Klein et al., 1988; Figure 4.3a). In both types of diabetes the incidence of retinopathy is higher if blood sugar is poorly controlled, and progression of retinopathy is also more common in those with worse control (Figure 4.3b). The incidence of proliferative disease and macular oedema are significantly reduced in those with blood sugar levels that are nearer normal levels (Figures 4.3c, 4.3d). These data suggest that better control of blood sugar would lead to a reduction in the incidence of blindness due to diabetes. Unfortunately, once diabetic retinopathy is well established, better control of blood sugar does not appear to slow progression of the disease (DCCT, 1993), and it is important that near normoglycaemia is established and maintained from diagnosis to prevent blindness in later life. Use of insulin Insulin use is associated with a higher prevalence of retinopathy (Dwyer et al., 1985). All Type 1 and some Type 2 diabetic individuals need insulin to control their blood sugar. It has been found that those using insulin develop more retinopathy than those using hypoglycaemic medication and diet alone. Both proliferative retinopathy (Palmberg et al., 1981; Klein et al., 1984c; Klein et al., 1989a) and macular oedema (Klein et al., 1984d) are more prevalent in those using insulin. (Figures 4.4, 4.5). Insulin use also influences the incidence of retinopathy. Over a 10-year period, retinopathy developed in more WESDR diabetic patients using insulin than in those
48
Diabetic Eye Disease
Figure 4.3 (a) Ten-year incidence of new retinopathy by quartiles of blood sugar levels at baseline. In all groups, the best blood sugar control is associated with the least retinopathy. (b) Ten-year progression of retinopathy by quartiles of blood sugar levels at baseline. Better blood sugar levels were associated with less progression of retinopathy. (c) Ten-year incidence of proliferative retinopathy by quartiles of blood sugar levels at baseline. Proliferative disease is significantly less with lower blood sugar levels. (d) Ten-year incidence of macular oedema by quartiles of blood sugar control at baseline. In all cases quartile 1 is the group with lowest blood sugar levels (best control), quartile 2 is the next level up, quartile 3 is higher still and quartile 4 is the group with the the highest blood sugar levels. All data from WESDR (Klein et al., 1988).
controlled by other means (Klein et al., 1994b). Proliferative retinopathy was also more common in patients using insulin (Figure 4.6). Other risk factors 1. Age is important to the prevalence of retinopathy. Any retinopathy is rare before puberty (Krolewski et al., 1986). Older age is
positively related to the presence of diabetic macular oedema in Type 1 and Type 2 diabetes (Klein et al., 1984d). Older age is also a recognized risk factor for severity of retinopathy in Type 1 patients (Moss et al., 1998). 2. Hypertension is an independent risk factor for diabetic retinopathy (UK Prospective Diabetes Study Group, 1998) and visual loss
Epidemiology of diabetic eye disease
Figure 4.4 Prevalence of proliferative retinopathy by type and control of diabetes. Data from WESDR (Klein et al., 1984a, 1984c).
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Figure 4.6 Ten-year incidence of proliferative retinopathy by duration of diabetes. Type 2 patients not using insulin have less risk of proliferative retinopathy developing, even after many years of diabetes. Data from WESDR (Klein et al., 1994).
5. Hormonal factors are important. The onset of puberty (Krolewski et al., 1986) and the pregnant state (Sunness, 1988) can result in progression of retinopathy.
Figure 4.5 Prevalence of macular oedema by duration of disease. Type 2 patients on insulin have the highest prevalence of macular oedema. Data from WESDR (Klein et al., 1984d).
(Sjolie et al., 1997). Abnormally high lipid levels in blood are associated with more retinal exudates (Chew et al., 1996) and progression of retinopathy (Dornan et al., 1982). 3. High alcohol intake is associated with a three-fold increased risk of more severe retinal disease (Moss et al., 1994). 4. Renal disease is also associated with the development and progression of retinopathy (Klein et al., 1993).
In the future, a better understanding of the risk factors will allow construction of a risk profile for each individual patient with regard to the various complications of diabetes. It would then be possible to discuss the risk to sight and how individuals might alter their lifestyle to reduce the development of complications. Fear of blindness may be the incentive needed to improve compliance with diet and good blood sugar control. More retinopathy in the future? The reported prevalence of diabetes is rising (O’Rahilly, 1997). In part this may be due to an increasing incidence of diabetes. There is also earlier detection of the disease with longer survival. In part it is because the number of elderly in the population is rising, and diabetes is more prevalent in the elderly. There is evidence that many of those with retinopathy are being referred too late for
50
Diabetic Eye Disease
effective treatment to prevent visual loss (Jones et al., 1988). In the future, with increasing numbers of diabetic people in society, screening and treatment strategies will need to improve if an associated rise in diabetes-related blindness is to be prevented.
existing backlog of untreated retinopathy. As measures to achieve better control of blood sugar reduce the incidence of retinal complications, fewer treatment centres would be required. Within two generations, the goal of eliminating the greater part of blindness due to diabetes could be achieved.
Possible remedies In recent years there have been a number of important developments in the understanding of the influence of metabolic factors on the progression of diabetic retinopathy. It is now recognized that diabetic retinopathy can be prevented by adherence to a regime which includes strict blood glucose control, low fat diet, regular exercise and avoidance of obesity. There may be other as yet unrecognized risk factors. The challenge is to motivate and educate those with diabetes, especially those who are without complications, so that retinopathy and other diabetic problems can be avoided.
Prevention of blindness In 1989, representatives from all European countries met to discuss diabetes care. They formulated The St Vincent Declaration, which outlined 5-year targets to reduce the morbidity and mortality from diabetes (The St Vincent Group, 1990). Data from epidemiological studies suggest two public health approaches to achieving these goals; better blood sugar control and better detection and treatment of diabetic retinopathy. The immediate introduction of universal systematic screening of diabetic individuals could achieve the St Vincent goal in the UK, since it is estimated that 60 per cent of diabetes-related blindness is preventable. Sight-threatening disease is often asymptomatic (Klein et al., 1986), and treatment is even more effective if it is carried out before advanced retinopathy develops (The Diabetic Retinopathy Study Research Group, 1979). To comply with the St Vincent declaration, the UK should introduce immediate regular fundus screening of all diabetic people. Initially, additional treatment facilities would need to be made available to catch up the
References Barnett, A. H., Eff, C., Leslie, R. D. G. and Pyke, D. A. (1981). Diabetes in identical twins: a study of 200 pairs. Diabetologia, 20, 87–93. Chew, E. Y., Klein, M. L., Ferris, F. L. et al. (1996). Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. ETDRS Report Number 22. Arch. Ophthalmol., 114, 1079–84. Evans, J. (1995). Causes of Blindness and Partial Sight in England and Wales 1990/91. Studies on Medical and Population Subjects No. 57. HMSO. Diabetes Control and Complications Trial Research Group (1993). 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., 329, 977–86. Dornan, T. L., Carter, R. D., Bron, A. J. et al. (1982). Low density lipoprotein cholesterol: an association with the severity of diabetic retinopathy. Diabetologia, 22, 167–70. Dwyer, M. S., Melton, I. J., Ballard, D. J. et al. (1985). Incidence of diabetic retinopathy and blindness: a population based study in Rochester, Minnesota. Diabetes Care, 8, 316–22. Foulds, W. S., McCuish, A., Barrie, T. et al. (1983). Diabetic retinopathy in the West of Scotland: Its detection and prevalence and cost-effectiveness of a proposed screening programme. Health Bull., 41, 318–26. Framingham Eye Study Monograph (1980). Surv. Ophthalmol., 24, 401–27. Ghafour, I. M., Allan, D. and Foulds, W. S. (1983). Common causes of blindness and visual handicap in the West of Scotland. Br. J. Ophthalmol., 67, 209–13. Houston, A. (1982). Retinopathy in the Poole area: an epidemiological enquiry. In: Advances in Diabetes Epidemiology (E. Eschwege, ed.), pp. 199–206. Elsevier Biomedical Press B.V. Jones, D., Dolben, J., Owens, D. R. et al. (1988). Nonmydriatic polaroid photography in screening for diabetic retinopathy: evaluation in a clinical setting. Br. Med. J., 296, 1029–30.
Epidemiology of diabetic eye disease Kahn, H. A. and Hiller, R. (1974). Blindness caused by diabetic retinopathy. Am. J. Ophthalmol., 78, 58–67. Klein, R., Klein, B. E. K. and Moss, S. E. (1984a). The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch. Ophthalmol., 102, 520–26. Klein, R., Klein, B. E. K. and Moss, S. E. (1984b). Visual impairment in diabetes. Ophthalmology, 91, 1–9. Klein, R., Klein, B. E. K., Moss, S. E. et al. (1984c). The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch. Ophthalmol., 102, 527–32. Klein, R., Klein, B. E. K., Moss, S. E. et al. (1984d). The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetic macular oedema. Ophthalmology, 91, 1464–74. Klein, B. E. K., Klein, R. and Moss, S. E. (1985). Prevalence of cataracts in a population based study of persons with diabetes mellitus. Ophthalmology, 92, 1191–6. Klein, R., Klein, B. E. K., Moss, S. E. et al. (1986). The validity of a survey question to study diabetic retinopathy. Am. J. Epidemiol., 124, 104–10. Klein, R., Klein, B. E. K., Moss, S. E. et al. (1988). Glycosylated haemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA, 260, 2864–71. Klein, R., Klein, B. E. K., Moss, S. E. et al. (1989a). The Wisconsin epidemiologic study of diabetic retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch. Ophthalmol., 107, 237–43. Klein, R., Klein, B. E. K., Moss, S. E. et al. (1989b). The Wisconsin epidemiologic study of diabetic retinopathy. X. Four year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch. Ophthalmol., 107, 244–9. Klein, R., Moss, S. E. and Klein, B. E. K. (1993). Is gross proteinuria a risk factor for the incidence of proliferative diabetic retinopathy? Ophthalmology, 100, 1140–46. Klein, R., Klein, B. E. K. and Moss, S. E. (1994a). Tenyear incidence of visual loss in a diabetic population. Ophthalmology, 101, 1061–70. Klein, R., Klein, B. E. K., Moss, S. E. and Cruickshanks, K. J. (1994b). The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XIV. Ten-year
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incidence and progression of diabetic retinopathy. Arch. Ophthalmol., 112, 1217–28. Krolewski, A. S., Warram, J. H., Rand, L. I. et al. (1986). Risk of proliferative diabetic retinopathy in juvenile-onset Type 1 diabetes: a 40-year followup study. Diabetes Care, 9, 443–52. Moss, S. E., Klein, R. and Klein, B. E. K. (1994). The association of alcohol consumption with the incidence and progression of diabetic retinopathy. Ophthalmology, 101, 1962–8. Moss, S. E., Klein, R. and Klein, B. E. K. (1998). The 14-year incidence of visual loss in a diabetic population. Ophthalmology, 105, 998–1003. National Society to Prevent Blindness (1993). Vision problems in the US: facts and figures. The American Academy of Ophthalmology Preferred Practice Patterns Series: Diabetic Retinopathy, 19–20. O’Rahilly, S. (1997). Non-insulin dependent diabetes mellitus: The gathering storm. Br. Med. J., 314, 955–9. Palmberg, P., Smith, M., Waltman, S. et al. (1981). The natural history of retinopathy in insulin dependent juvenile-onset diabetes. Ophthalmology, 88, 613–18. Sjolie, A. K., Stephenson, J., Aldington, S. et al. (1997). Retinopathy and vision loss in insulin dependent diabetes in Europe. The EURODIAB IDDM Complications Study. Ophthalmology, 104, 252–60. Stolk, R. P., Vingerling, J. R., de Jong, P. T. V. M. et al. (1995). Retinopathy, glucose and insulin in an elderly population. Diabetes, 44, 11–15. The Rotterdam Study. Sunness, J. S. (1998). The pregnant woman’s eye. Surv. Ophthalmol., 32, 219–38. The Diabetic Retinopathy Study Research Group (1979). Four risk factors for severe visual loss in diabetic retinopathy. The third report from the Diabetic Retinopathy Study. Arch. Ophthalmol., 97, 654–5. The St Vincent Group (1990). Diabetes care and research in Europe. Diab. Med., 7, 360. UK Prospective Diabetes Study Group (1998). Tight blood pressure control and risk of macrovascular complications in type 2 diabetes (UKPDS 38). Br. Med. J., 317, 713–20. Von Jaeger, Q. E. (1856). Beitraege zur Pathologie des Auges. Wein. Wilson, J. (1980). World Blindness and its Prevention, pp. 1–13. OUP.
Epidemiology of diabetic eye disease Gillian C. Vafidis
Introduction Diabetic eye disease is an important cause of world blindness (Ghafour et al., 1983; National Society to Prevent Blindness, 1993). The study of its epidemiology improves our understanding of diabetic eye disease and suggests ways in which visual loss may be prevented. The first report of retinal problems in diabetes was by Von Jaeger in Vienna in 1856. Since that time there have been a number of epidemiological studies concerned with dia-
betic-related eye problems (Stolk et al., 1995; Framingham Eye Study, 1980; Houston, 1982; Foulds et al., 1983), the most comprehensive being The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), which has reported on over 2300 diabetic inhabitants of Southern Wisconsin, United States (USA) over the last 14 years (Klein et al., 1984a). The findings of this study provide much of the statistical data discussed in this chapter. Table 4.1 defines the epidemiological terms used.
Table 4.1 Definition of epidemiological terms Term
Definition
Epidemiology
The study of patterns of diseases within populations
Prevalence
The number of cases in a given population at a single point in time
Incidence
The number of new cases in a specified population over a specified time period
Type 1 diabetes
Diabetes diagnosed before the age of 30 years, controlled by insulin injections
Type 2 diabetes
Diabetes diagnosed at or after the age of 30 years, controlled by insulin injection, hypoglycaemic medication or diet alone
Risk factors
Factors that increase the chances of an individual or population developing a specified disease or complication
Relative risk
An assessment of the influence of a risk factor on the rate (or risk) of an event occurring. It measures the strength of an association between a risk factor and disease, but cannot prove a causal relationship between the risk factor and disease
Odds ratio
An approximation to relative risk. It compares the risk of disease in someone with a given risk factor to that in someone without
Epidemiology of diabetic eye disease
Epidemiology of blindness in diabetes Diabetes is the leading cause of blindness in the working population in developed countries. It accounts for 7–8 per cent of all blind registrations and for 1000 new blindness registrations in the UK each year (Evans, 1995), most of which are for diabetic retinopathy. It is the single most important cause of preventable blindness, and it has been estimated that individuals with diabetes have a 25 times higher risk of going blind than those without the disease (Kahn and Hiller, 1974). Diabetic retinopathy causes blindness in one of two ways, either by direct involvement of the macular capillaries or from the complications of proliferative disease. In young patients, where diabetes is diagnosed before the age of 30 years (Type 1 diabetes), blindness is usually as a consequence of proliferative disease. In people diagnosed after the age of 30 years (Type 2 disease), visual impairment is most frequently due to cataract and blindness from diabetic macular oedema (Klein et al., 1984b). Type 2 disease is associated with the highest incidence of blindness, with 4 per cent of those using insulin and 4.8 per cent of those not using insulin going blind over a 10-year period (Klein et al., 1994a). Cataract is the major cause of blindness in the developing world (Wilson, 1980). Where malnutrition is common diabetes is uncommon, but as life expectancy and standards of living rise it is anticipated that diabetes and consequently diabetic retinopathy will become a major cause of blindness in the developing world.
Prevalence of diabetic eye disease Diabetes is estimated to affect 100 million people world-wide. In western countries the prevalence is between 2 and 4 per cent of the population. The majority have ‘maturity onset’ Type 2 disease, and only 10–15 per cent have Type 1 diabetes, i.e. they developed the disease in childhood or in young adult life. The age at onset determines the frequency and nature of diabetic eye complications.
45
The major ocular complication of diabetes is retinopathy, which is present in one-third of all individuals with diabetes. Younger onset patients have the highest prevalence and the most severe retinopathy. Less frequent and less severe diabetic retinopathy is found in older onset patients not using insulin (Kahn and Hiller, 1974). The ocular consequences of diabetes are not confined to retinopathy, and include cataract and cranial nerve palsies. Significant cataract was found in 60 per cent of the diabetic population aged 30–54 years in the WESDR (Klein et al., 1985), a five-fold increased prevalence over that of a control population. Intraocular inflammation, glaucoma and retinal vascular disease are also more commonly found in diabetic patients than in a nondiabetic population.
Diabetic retinopathy Prevalence of diabetic retinopathy Diabetic retinopathy principally affects small retinal blood vessels. Its onset and development are related to a number of factors: the type and control of diabetes, concurrent circulatory, hormonal and metabolic problems, and the race, age, sex and diet of the individual. For both Type 1 and Type 2 diabetes, a consistent predictor of the presence of retinopathy is the duration of the systemic disease. The longer an individual has had diabetes, the more likely is diabetic retinopathy. After 5 years of diabetes, the overall prevalence of any retinopathy is 25 per cent. After 10 years this figure has risen to 60 per cent, and by 15 years 80 per cent of all diabetic individuals will have retinopathy. Type 1 patients demonstrate the strongest relationship between diabetic retinopathy and duration of disease (Palmberg et al., 1981). At diagnosis of Type 1 disease retinopathy is unusual, but by 15 years of diabetes, it is an almost universal finding. A similar association with disease duration occurs in Type 2 diabetes, although significant retinopathy is already present at diagnosis in up to 30 per cent
46
Diabetic Eye Disease
Figure 4.1 Prevalence of diabetic retinopathy with type and duration of disease. The frequency of retinopathy at diagnosis is higher in Type 2 disease. The frequency of retinopathy in Type 1 disease is almost 100 per cent after 15 years’ duration. Data from WESDR (Klein et al., 1984a, 1984c).
Figure 4.2 Ten-year incidence and progression of retinopathy with type of diabetes. The incidence of new retinopathy, the progression of existing retinopathy and the incidence of proliferative retinopathy are higher in patients using insulin. Data from WESDR (Klein et al., 1994).
and the frequency of retinopathy never reaches the high prevalence levels of Type 1 disease, even after 25 years (Klein et al., 1984c) (Figure 4.1)
retinopathy at the start developed it over a 4-year period. Significant progression of retinopathy also occurred in this group. One in ten of those with non-proliferative disease progressed to proliferative retinopathy within 4 years (Klein et al., 1989a). In people with Type 2 disease using insulin who did not have any retinopathy at the start of the study, nearly 50 per cent developed new retinopathy and 7 per cent developed proliferative disease after 4 years. Even in Type 2 diabetes controlled on hypoglycaemic medication and/or diet, a third developed new retinopathy and a quarter had progression of existing retinopathy (Klein et al., 1989b). The 10-year incidence and progression of retinopathy is shown in Figure 4.2.
Incidence of retinopathy The incidence of retinopathy is an index of the development of new or progressive retinal disease occurring within a diabetic population in a specified period of time. Incidence data are especially useful for planning health resources. It is important to be able to estimate the number of people within a population who are likely to develop sight-threatening disease over a given time interval so that appropriate health provision can be planned. The Wisconsin Study looked at the number of new cases of retinopathy in the study population, and also at progression of retinopathy in those with pathology at the start of the study. When comparing Type 1 with Type 2 diabetes, they found that the highest incidence of new retinopathy was in Type 1 patients. Nearly 60 per cent of Type 1 patients without
Risk factors In a given individual, the risk of diabetes is a function of genetic inheritance, age, obesity, level of physical activity, cigarette smoking and alcohol use. Risk factors for diabetic retinopathy have also been identified. These factors
Epidemiology of diabetic eye disease
47
Table 4.2 Known risk factors for the development and progression of diabetic retinopathy Type 1 (age at onset less than 30 years)
Type 2 (age at onset over 30 years)
Higher blood sugar levels Higher diastolic blood pressure Gross proteinuria Increased age Male sex
Higher blood sugar levels Higher systolic blood pressure Presence of proteinuria Use of insulin
influence the type and progression of disease, and offer the hope that by their manipulation the onset of retinopathy may be delayed or prevented altogether. Genetic risk factors Genetic risk factors are important in both Type 1 and Type 2 diabetes. Specific chromosomal patterns appear to correspond to the development of diabetic retinopathy in Type 1 diabetes. For example, the presence of HLA-B15 histocompatibility antigen increases four-fold the risk of developing retinopathy. Identical twin studies in Type 2 diabetes have shown that equivalent grades of retinopathy in sibling pairs occur significantly more often than can be attributed to chance alone (Barnett et al., 1981). Blood sugar control Metabolic risk factors are highly significant in the development and progression of diabetic retinopathy. Table 4.2 lists the risk factors for the development and progression of retinopathy. Uncontrolled blood sugar is the most important determinant of the development and progression of diabetic retinopathy so far identified. A large trial in the USA, the Diabetes Control and Complications Trial (DCCT, 1993), found that strict control of blood sugar in Type 1 diabetes reduced the 5-year risk of new retinopathy by 76 per cent and the risk of progression of existing retinopathy by 54 per cent. In Type 2 disease, uncontrolled hyperglycaemia is also recognized to be a risk factor for retinopathy. Data from the WESDR shows the association of 10-year incidence of retinopathy with blood sugar control
at baseline for both Type 1 and Type 2 patients (Klein et al., 1988; Figure 4.3a). In both types of diabetes the incidence of retinopathy is higher if blood sugar is poorly controlled, and progression of retinopathy is also more common in those with worse control (Figure 4.3b). The incidence of proliferative disease and macular oedema are significantly reduced in those with blood sugar levels that are nearer normal levels (Figures 4.3c, 4.3d). These data suggest that better control of blood sugar would lead to a reduction in the incidence of blindness due to diabetes. Unfortunately, once diabetic retinopathy is well established, better control of blood sugar does not appear to slow progression of the disease (DCCT, 1993), and it is important that near normoglycaemia is established and maintained from diagnosis to prevent blindness in later life. Use of insulin Insulin use is associated with a higher prevalence of retinopathy (Dwyer et al., 1985). All Type 1 and some Type 2 diabetic individuals need insulin to control their blood sugar. It has been found that those using insulin develop more retinopathy than those using hypoglycaemic medication and diet alone. Both proliferative retinopathy (Palmberg et al., 1981; Klein et al., 1984c; Klein et al., 1989a) and macular oedema (Klein et al., 1984d) are more prevalent in those using insulin. (Figures 4.4, 4.5). Insulin use also influences the incidence of retinopathy. Over a 10-year period, retinopathy developed in more WESDR diabetic patients using insulin than in those
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Diabetic Eye Disease
Figure 4.3 (a) Ten-year incidence of new retinopathy by quartiles of blood sugar levels at baseline. In all groups, the best blood sugar control is associated with the least retinopathy. (b) Ten-year progression of retinopathy by quartiles of blood sugar levels at baseline. Better blood sugar levels were associated with less progression of retinopathy. (c) Ten-year incidence of proliferative retinopathy by quartiles of blood sugar levels at baseline. Proliferative disease is significantly less with lower blood sugar levels. (d) Ten-year incidence of macular oedema by quartiles of blood sugar control at baseline. In all cases quartile 1 is the group with lowest blood sugar levels (best control), quartile 2 is the next level up, quartile 3 is higher still and quartile 4 is the group with the the highest blood sugar levels. All data from WESDR (Klein et al., 1988).
controlled by other means (Klein et al., 1994b). Proliferative retinopathy was also more common in patients using insulin (Figure 4.6). Other risk factors 1. Age is important to the prevalence of retinopathy. Any retinopathy is rare before puberty (Krolewski et al., 1986). Older age is
positively related to the presence of diabetic macular oedema in Type 1 and Type 2 diabetes (Klein et al., 1984d). Older age is also a recognized risk factor for severity of retinopathy in Type 1 patients (Moss et al., 1998). 2. Hypertension is an independent risk factor for diabetic retinopathy (UK Prospective Diabetes Study Group, 1998) and visual loss
Epidemiology of diabetic eye disease
Figure 4.4 Prevalence of proliferative retinopathy by type and control of diabetes. Data from WESDR (Klein et al., 1984a, 1984c).
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Figure 4.6 Ten-year incidence of proliferative retinopathy by duration of diabetes. Type 2 patients not using insulin have less risk of proliferative retinopathy developing, even after many years of diabetes. Data from WESDR (Klein et al., 1994).
5. Hormonal factors are important. The onset of puberty (Krolewski et al., 1986) and the pregnant state (Sunness, 1988) can result in progression of retinopathy.
Figure 4.5 Prevalence of macular oedema by duration of disease. Type 2 patients on insulin have the highest prevalence of macular oedema. Data from WESDR (Klein et al., 1984d).
(Sjolie et al., 1997). Abnormally high lipid levels in blood are associated with more retinal exudates (Chew et al., 1996) and progression of retinopathy (Dornan et al., 1982). 3. High alcohol intake is associated with a three-fold increased risk of more severe retinal disease (Moss et al., 1994). 4. Renal disease is also associated with the development and progression of retinopathy (Klein et al., 1993).
In the future, a better understanding of the risk factors will allow construction of a risk profile for each individual patient with regard to the various complications of diabetes. It would then be possible to discuss the risk to sight and how individuals might alter their lifestyle to reduce the development of complications. Fear of blindness may be the incentive needed to improve compliance with diet and good blood sugar control. More retinopathy in the future? The reported prevalence of diabetes is rising (O’Rahilly, 1997). In part this may be due to an increasing incidence of diabetes. There is also earlier detection of the disease with longer survival. In part it is because the number of elderly in the population is rising, and diabetes is more prevalent in the elderly. There is evidence that many of those with retinopathy are being referred too late for
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Diabetic Eye Disease
effective treatment to prevent visual loss (Jones et al., 1988). In the future, with increasing numbers of diabetic people in society, screening and treatment strategies will need to improve if an associated rise in diabetes-related blindness is to be prevented.
existing backlog of untreated retinopathy. As measures to achieve better control of blood sugar reduce the incidence of retinal complications, fewer treatment centres would be required. Within two generations, the goal of eliminating the greater part of blindness due to diabetes could be achieved.
Possible remedies In recent years there have been a number of important developments in the understanding of the influence of metabolic factors on the progression of diabetic retinopathy. It is now recognized that diabetic retinopathy can be prevented by adherence to a regime which includes strict blood glucose control, low fat diet, regular exercise and avoidance of obesity. There may be other as yet unrecognized risk factors. The challenge is to motivate and educate those with diabetes, especially those who are without complications, so that retinopathy and other diabetic problems can be avoided.
Prevention of blindness In 1989, representatives from all European countries met to discuss diabetes care. They formulated The St Vincent Declaration, which outlined 5-year targets to reduce the morbidity and mortality from diabetes (The St Vincent Group, 1990). Data from epidemiological studies suggest two public health approaches to achieving these goals; better blood sugar control and better detection and treatment of diabetic retinopathy. The immediate introduction of universal systematic screening of diabetic individuals could achieve the St Vincent goal in the UK, since it is estimated that 60 per cent of diabetes-related blindness is preventable. Sight-threatening disease is often asymptomatic (Klein et al., 1986), and treatment is even more effective if it is carried out before advanced retinopathy develops (The Diabetic Retinopathy Study Research Group, 1979). To comply with the St Vincent declaration, the UK should introduce immediate regular fundus screening of all diabetic people. Initially, additional treatment facilities would need to be made available to catch up the
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incidence and progression of diabetic retinopathy. Arch. Ophthalmol., 112, 1217–28. Krolewski, A. S., Warram, J. H., Rand, L. I. et al. (1986). Risk of proliferative diabetic retinopathy in juvenile-onset Type 1 diabetes: a 40-year followup study. Diabetes Care, 9, 443–52. Moss, S. E., Klein, R. and Klein, B. E. K. (1994). The association of alcohol consumption with the incidence and progression of diabetic retinopathy. Ophthalmology, 101, 1962–8. Moss, S. E., Klein, R. and Klein, B. E. K. (1998). The 14-year incidence of visual loss in a diabetic population. Ophthalmology, 105, 998–1003. National Society to Prevent Blindness (1993). Vision problems in the US: facts and figures. The American Academy of Ophthalmology Preferred Practice Patterns Series: Diabetic Retinopathy, 19–20. O’Rahilly, S. (1997). Non-insulin dependent diabetes mellitus: The gathering storm. Br. Med. J., 314, 955–9. Palmberg, P., Smith, M., Waltman, S. et al. (1981). The natural history of retinopathy in insulin dependent juvenile-onset diabetes. Ophthalmology, 88, 613–18. Sjolie, A. K., Stephenson, J., Aldington, S. et al. (1997). Retinopathy and vision loss in insulin dependent diabetes in Europe. The EURODIAB IDDM Complications Study. Ophthalmology, 104, 252–60. Stolk, R. P., Vingerling, J. R., de Jong, P. T. V. M. et al. (1995). Retinopathy, glucose and insulin in an elderly population. Diabetes, 44, 11–15. The Rotterdam Study. Sunness, J. S. (1998). The pregnant woman’s eye. Surv. Ophthalmol., 32, 219–38. The Diabetic Retinopathy Study Research Group (1979). Four risk factors for severe visual loss in diabetic retinopathy. The third report from the Diabetic Retinopathy Study. Arch. Ophthalmol., 97, 654–5. The St Vincent Group (1990). Diabetes care and research in Europe. Diab. Med., 7, 360. UK Prospective Diabetes Study Group (1998). Tight blood pressure control and risk of macrovascular complications in type 2 diabetes (UKPDS 38). Br. Med. J., 317, 713–20. Von Jaeger, Q. E. (1856). Beitraege zur Pathologie des Auges. Wein. Wilson, J. (1980). World Blindness and its Prevention, pp. 1–13. OUP.