Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

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diabetes [26], with signs of proliferative disease in 1.6% and macular edema in 5.5%. Among persons with newly diagnosed diabetes (i.e., undetected diabetes), retinopathy was present in about 16%. The Australian Diabetes Obesity and Lifestyle (AusDiab) study examined 11,247 adults aged 25 years or older from 42 randomly selected urban and rural communities [33]. Overall, 25% of participants with known diabetes were found to have retinopathy, including 2% with proliferative retinopathy. As in other studies, the prevalence of retinopathy was strongly related to the duration of diabetes, with a prevalence of 9.2% among those with duration less than 5 years, 23% for durations between 5 and 9 years, 33% for durations between 10 and 19 years, and 57% for those with duration of 20 or more years. In fact, after accounting for duration of diabetes, the prevalence findings from these three Australian studies were relatively similar.

In many Asian countries, the prevalence of diabetes has increased substantially over the past few decades [34–38]. In Singapore, for example, serial population surveys in 1975, 1985, and 1992 showed increasing prevalence rates of diabetes of 2%, 4.7%, and 8.6%, respectively, in the population between the ages of 15 and 69 years [37,38]. However, there remains limited information on the epidemiology of retinopathy among Asians. The Aravind Eye Disease Survey in southern India reported a retinopathy prevalence of 27% in a population aged 50 years or older with self-reported diabetes [39 ], similar to the 22% prevalence reported from another population-based study in an urban population in Hyderabad, India [40]. These rates are similar to those reported in the U.S. and elsewhere.

Incidence and Progression of Diabetic Retinopathy. There are few long-term data on the incidence and natural history of diabetic retinopathy. In the WESDR, the 4-year incidence of retinopathy in the entire cohort was 40% [41,42]. The 4-year incidence and progression rates of diabetic retinopathy in the WESDR are presented in Figure 5.2. The younger-onset group using insulin had the highest 4-year incidence, rate of progression, and rate of progression to proliferative retinopathy, while the older-onset group not using insulin had the lowest rates.

In the WESDR, the 10-year incidence of new retinopathy was 76% in the younger-onset group, 69% in the older-onset group on insulin and 53% in the non-insulin treated older-onset group [43]. The 10-year incidence of macular edema was 20% in the younger-onset group, 25% in the older-onset group on insulin and 14% in the older-onset group not on insulin (Fig. 5.3) [44]. WESDR also reported on the progression of retinopathy in diabetic persons with retinopathy at baseline. The 10-year progression to proliferative retinopathy was 30% in the younger-onset group, 24% in the older-onset group on insulin, and 10% in the older-onset group not on insulin [43]. Based on the WESDR data, it is estimated that each year, of the 10 million Americans with known diabetes mellitus, 96,000 will develop proliferative retinopathy, and 121,000 will develop macular edema.

There are few other long-term population-based incidence data using objective measures to detect retinopathy to compare with these findings [45–52]. In the United Kingdom Prospective Diabetes Study (UKPDS), a multicenter randomized clinical trial of the effects of targeted levels of glycemia on complications of diabetes, the 6-year incidence of retinopathy was 41% in the 1216 patients with

Figure 5.2. Four-Year Incidences of Any Retinopathy, Improvement or Progression of Retinopathy, and Progression to proliferative diabetic retinopathy in Wisconsin Epidemiologic Study Diabetic Retinopathy, 1980–1986. (Source: Modified from Klein R, Klein BEK, Moss SE, et al. 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. 1989;107:237–243; and Klein R, Klein BEK, Moss SE, et al. 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. 1989;107:244–249. Copyrighted © 1989 with permission from American Medical Association. All rights reserved.)

newly diagnosed type 2 diabetes without retinopathy at baseline [51]. In the United Kingdom Prospective Diabetes Study (UKPDS), a multicenter randomized clinical trial of the effects of targeted levels of glycemia on complications of diabetes, the 6-year incidence of retinopathy was 41% in the 1,216 patients with newly diagnosed type 2 diabetes without retinopathy at baseline [51]. Of those with retinopathy at baseline, 30% progressed by two or more steps on the ETDRS scale over the 6- year period. As with WESDR, the incidence and progression of retinopathy was dependent on the level of hyperglycemia. Of those with retinopathy at baseline, 30% progressed by two or more steps on the ETDRS scale over the 6-year period. The Liverpool Diabetic Eye Study assessed a cohort of patients registered with general practices within the Liverpool Health Authority to investigate the yearly and cumulative incidence of any retinopathy in persons with type 2 diabetes [52]. The annual incidence of sight-threatening retinopathy in diabetic persons without retinopathy at baseline was 0.3% in the first year, rising to 1.8% in the fifth year, suggesting that the incidence of retinopathy, like the prevalence, increases with duration of diabetes [52].

Time Trends in the Epidemiology of Diabetic Retinopathy. There have been some suggestions that over the past 25 years, better recognition and management of retinopathy risk factors based on evidence from the Diabetes Control and

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Figure 5.3. Four-Year Incidences of Macular Edema and clinically significant macular edema, by Diabetes Group, Wisconsin Epidomiologic Study of Diabetic Retinopathy, 1980–1986. (Source: Reprinted from Klein R, Moss SE, Klein BEK, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy, XI: The incidence of macular edema. Ophthalmology. 1989;96:1501– 1510. Copyright © 1989 with permission from American Academy of Ophthalmology. All rights reserved.)

Complications Trial (DCCT) and UKPDS and the institution of structured retinopathy screening programs have led to a decline in both the prevalence and incidence of moderate to severe microvascular diabetic complications.

Studies conducted in contemporary populations have suggested this to be the case, although differences in study design, population characteristics, and definitions of diabetes and retinopathy between earlier and newer studies make it difficult to draw definitive conclusions. For example, data from both the UKPDS [51] and the Liverpool Diabetic Eye Study [52] show lower incidence rates for retinopathy, particularly sight-threatening retinopathy, than was reported previously in the WESDR and studies in the early 1980s [53]. A recent study assessed the age at which retinopathy was first diagnosed in a sample of patients with type 1 diabetes and showed that the median diabetes duration until the first occurrence of retinopathy was 16.6 years [54], which is longer than reported in previous studies. Data from Sweden indicated that the prevalence of retinopathy appeared to be decreasing in the past decade [46]. The meta-analysis review showed that estimates of retinopathy prevalence was about 10% to 20% lower in the 7 later studies as compared to WESDR [22].

These data provide supporting evidence that improvements in diabetes management and improved levels of metabolic and blood pressure control may have had a positive impact in reducing the prevalence and incidence of retinopathy.

Retinopathy in Non-Diabetic Persons. There is increasing recognition that typical lesions of early retinopathy (retinal microaneuryms, hemorrhages and cotton wool

spots) are also commonly seen in persons without clinically diagnosed diabetes [55]. Studies using fundus photographs to evaluate retinopathy have reported prevalence rates of up to 14% in some populations [56–59]. Prospective data from the Beaver Dam and Blue Mountains Eye Studies show that these retinopathy signs developed in 6% to 10% of nondiabetic persons over a 5-year period [59,60].

The risk factors associated with retinopathy signs in nondiabetic persons remain unclear. Various studies show that these retinopathy signs may be related to impaired glucose tolerance [61–63], components related to the metabolic syndrome [64] and hypertension [65–67]. However, population-based studies in nondiabetic adult patients show that while hypertension is strongly associated with prevalence of retinal hemorrhages and microaneurysms [55,56,58], higher blood pressure is not associated with the incidence of these retinopathy signs [47,60].

Few studies have investigated if these retinopathy signs are preclinical markers of diabetes. In the Atherosclerosis Risk in Communities (ARIC) study, retinopathy signs in nondiabetic persons were not significantly associated with the subsequent incidence of diabetes, except among individuals with a positive family history of diabetes [68]. This suggests that in persons with underlying predisposition to diabetes, retinopathy signs may be markers of underlying abnormalities in glucose metabolism or microvascular disease.

DEMOGRAPHIC VARIATIONS

Age. In type 1 diabetes, the prevalence and severity of diabetic retinopathy appear to increase with age. In the WESDR, diabetic retinopathy was infrequent in persons younger than 13 years of age, irrespective of the duration of the disease [9]. The 4-year incidence and progression of retinopathy also increased with age, rising steadily until 15 to 19 years of age, after which there was a gradual decline [41]. Because none of the participants younger than 13 years of age at baseline developed proliferative retinopathy at the 4-year follow-up. These data are supported by similar observations in other cohorts with type 1 diabetes [69,70]. It has therefore been recommended that retinopathy screening may not be necessary in young children with type 1 diabetes [71].

Among persons with older-onset type 2 diabetes, the risk of retinopathy may decrease with age. In the older-onset group taking insulin in WESDR, the 4-year incidence of retinopathy and progression of retinopathy was lower in older compared to younger persons [42]. For those not taking insulin, the 4-year rate of progression to proliferative retinopathy decreased with increasing age. In fact, few participants 75 years or older developed proliferative retinopathy over the 10 years of follow-up in WESDR [43].

These findings are supported by data from other population-based studies [44,45]. In a study of people with type 2 diabetes in Rochester, Minnesota, a lower incidence of retinopathy with increasing age in diabetic people older than 60 years of age was found [12]. It is possible that older persons have less severe retinopathy. Alternatively, these findings may indicate selective mortality, that is, older persons with severe retinopathy are more likely to die and are not followed-up.

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Gender. Epidemiological studies have not shown a consistent pattern of gender variation in either prevalence or incidence of retinopathy. In the WESDR, younger-onset men were more likely to have proliferative retinopathy than younger women [8], but there were no significant differences in the incidence or progression of diabetic retinopathy between younger-onset men and women [41,43]. In older-onset diabetes participants in the WESDR, there were no significant differences by gender in either the prevalence or incidence of retinopathy [9,42,43].

Race/Ethnicity. There is a substantial body of evidence that the prevalence of diabetes and diabetic retinopathy varies among racial/ethnic groups [13,16,17,19–22].

Studies comparing rates of retinopathy between African Americans and whites have consistently shown a higher prevalence of diabetic retinopathy in African Americans. Three population-based studies, the National Health and Nutrition Examination Survey III (NHANES III) [17], the ARIC study [20], and the Cardiovascular Health Study [21], showed that retinopathy was more prevalent in African Americans with type 2 diabetes than in whites. In the NHANES III, the higher prevalence of retinopathy in African Americans compared to whites disappeared after controlling for retinopathy risk factors, such as glycemic and blood pressure levels [17]. Likewise, in the ARIC study, the higher prevalence of retinopathy in African Americans (28%) than whites (17%) was largely explained by black–white differences in glycemic control, duration of diabetes, and blood pressure [20]. Thus, the higher prevalence of retinopathy in African Americans with type 2 diabetes is partly due to poorer metabolic and blood pressure control in this racial group, and reinforces the need to achieve tight glycemic and blood pressure control in African Americans.

Similar to African Americans, Hispanics have been reported to have higher prevalence of both diabetes and diabetic retinopathy [22]. However, the higher prevalence in Hispanics is not entirely explained by higher frequency of retinopathy risk factors in this racial group. Haffner and colleagues showed that even in multivariate analysis controlling for glycemia and other risk factors, retinopathy in Hispanics living in San Antonio was 2.4 times higher than non-Hispanic whites in the WESDR [13]. Similarly, in the NHANES III, retinopathy was significantly more frequent among adult Hispanics than non-Hispanic whites with type 2 diabetes, despite controlling for duration of diabetes, glycosylated hemoglobin level, blood pressure, and type of antihyperglycemic medication used [17]. Varma et al. recently found Mexican Americans living in Los Angeles to have a higher prevalence of proliferative retinopathy and macular edema than whites living in Beaver Dam, Wisconsin [72].

Native American groups, such as the Pima Indians, have long been known to have a higher prevalence of type 2 diabetes and to have more advanced retinopathy for a given duration of diabetes as compared to whites [73,74]. It has been suggested that Native American groups may have been exposed to longer periods of more severe hyperglycemia at a younger age than whites with type 2 diabetes. In addition, even among different Native American groups, the prevalence and severity of retinopathy appears to vary [75–77], possibly related to different levels or impact of retinopathy risk factors or genetic differences.

Few studies have examined the prevalence of retinopathy in Asian Americans [78,79]. Retinopathy in second generation Japanese American males (Nisei), 12%, was significantly lower than that reported in the diabetes clinic in Tokyo (49% among patients with an onset of diabetes from 20 to 59 years of age and 47% among those with an onset after 59 years of age) and in whites reported in the WESDR (36%) [9,80]. One of the few studies to directly compare rates of retinopathy among different racial/ethnic groups in the U.S. was the Multi-Ethnic Study of Atherosclerosis, which examined the prevalence of diabetic retinopathy among whites, African Americans, Hispanics and Chinese Americans aged 45 years and older [81]. This study showed that the prevalence of retinopathy was similar between African Americans (37%) and Hispanics (37%) and was lower in whites (25%) and Chinese Americans (26%).

In summary, there is substantial variation in the rates of diabetic retinopathy among racial/ethnic groups, but the underlying reasons for these differences are complex, and likely to reflect a combination of variations in health care access, genetic susceptibility and other risk factors for retinopathy, such as duration of diabetes, levels of glycemia, and blood pressure. Nonetheless, it is worth noting that in many studies, controlling for these known risk factors had only a minor effect on the higher retinopathy prevalence among racial/ethnic groups, suggesting that other unmeasured possible risk factors (genetic or otherwise) may account for these variations.

RISK FACTORS

Duration of Diabetes. The strongest predictor for the prevalence of retinopathy in persons with type 1 and type 2 diabetes is the duration of diabetes. In the youngeronset group in the WESDR, the prevalence of any retinopathy was 8% among participants with diabetes duration of 3 years, 25% for 5 years, 60% for 10 years, and 80% for 15 years [8]. The prevalence of proliferative retinopathy was 0% for those with diabetes duration of 3 years, increasing to 25% for 15 years.

In general, the higher prevalence of retinopathy at presentation in type 2 diabetes as compared to type 1 diabetes is a reflection of the longer duration of diabetes before diagnosis in patients with type 2 diabetes. Extrapolating data of retinopathy prevalence for different durations of diabetes from older-onset participants in the WESDR and from a study in Australia, Harris et al. estimated that the onset of detectable retinopathy occurred approximately 4 to 7 years before diagnosis of type 2 diabetes [82].

The incidence of retinopathy also increases with increasing duration of diabetes [41–43,83]. The 4-year incidence of proliferative retinopathy in the WESDR younger-onset group increased from 0% among participants with diabetes duration of 5 years to 28% for those with diabetes duration of 13 to 14 years. After 15 years of diabetes, the incidence of proliferative retinopathy remained stable. In the older-onset WESDR group, 2% of those with diabetes for less than 5 years and 5% of those with diabetes for 15 or more years who were not taking insulin at baseline developed signs of proliferative disease at the 4-year follow-up [58].

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Other epidemiological and clinical studies have corroborated the WESDR findings. For example, a Swedish study of type 1 diabetic persons showed an increase in prevalence of retinopathy from 4% in patients with duration of diabetes less than 2 years to 32% among those with duration of diabetes between 10 and 12 years [84].

Hyperglycemia. One of the most important predictive factors for diabetic retinopathy is the level of glycemic control [8,9,12,14,15,20,27,28,30,33,85–94]. The WESDR showed that both the younger-onset and older-onset patients with diabetes who had no retinopathy had significantly lower mean glycosylated hemoglobin values than those patients with retinopathy [93]. Patients with higher glycosylated hemoglobin values were shown to have a higher risk of retinopathy, such that those with mean HbA1c levels over 12% were 3.2 times more likely to have retinopathy after 4 years than subjects with HbA1c levels under 12% [93].

Two landmark multicentered clinical trials, the DCCT [3,90,95,96] and the UKPDS [4,5], assessed the relationship between glycemic control and vascular complications of diabetes (Table 5.1).

The DCCT randomized patients with type 1 diabetes to strict glycemic control (intensive group) or conventional treatment. Over a 6.5 year period, intensive glycemic control reduced the incidence of retinopathy by 76% and progression from early to advanced retinopathy by 54% [3]. For each 10% decrease in HbA1c (e.g., from 9.0% to 8.1% or from 8.0% to 7.2%) there was a 39% decrease in risk of retinopathy. In the DCCT, tight glycemic control was associated with an early worsening in retinopathy in the first year of treatment in the intensive control [90], consistent with observations in other studies [97]. However, after 18 months, the early worsening in retinopathy reversed and the overall beneficial effect of intensive treatment increased with time. It is unclear whether a slower correction of hyperglycemia in poorly controlled diabetic patients may reduce the risk of early worsening.

The DCCT addressed three important clinical questions regarding diabetic retinopathy. First, it examined whether there is a threshold glycosylated hemoglobin level (suggested to be around 8%) above which the risk of retinopathy increased markedly [98]. The DCCT study could not demonstrate any definite threshold level. This was supported by the EURODIAB prospective complications study that showed no glycemic threshold for incident retinopathy in 764 patients with type 1 diabetes followed for an average of 7 years [99]. Second, the DCCT examined whether intensive glycemic control is more beneficial when started earlier in the course of type 1 diabetes [96]. The study found that in the intensive therapy group, the progression of retinopathy was lower among patients with retinopathy for less than 2.5 years (7%) compared to those with more than 2.5 years (20%). This supports the concept that beginning intensive treatment earlier in the course of diabetes, prior to the onset of diabetic retinopathy, may have added benefit. Third, the DCCT, via the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up study of the DCCT cohort, addressed the issue of

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From the results of the DCCT, it was estimated that intensive therapy would result in a “gain of 920,000 years of sight, 691,000 years free from end-stage renal disease, 678,000 years free from lower extremity amputation, and 611,000 years of life at an additional cost of $4.0 billion over the lifetime” of the 120,000 persons with type 1 diabetes in the U.S. who meet DCCT eligibility criteria [3]. The incremental cost per year of life gained was $28,661, and, when adjusted for quality of life, intensive therapy costs $19,987 per quality of life year gained, similar to cost effectiveness of other medical interventions for chronic diseases in the U.S.

In the UKPDS, intensive therapy reduced the risk of retinopathy progression by 21% and reduced the need for laser photocoagulation by 29% as compared to conventional treatment [4,101]. A 1% reduction in mean HbA1c level was associated with a reduction in the risk of any microvascular complications by 37%. Intensive treatment, however, did not appear to have a significant impact on the risk for macrovascular events [5]. In the UKPDS, a 6-year sub-study using detailed grading of retinal photographs showed that the development of retinopathy was strongly influenced by baseline glycemia and glycemic exposure over the follow-up period [51].

There is some suggestion that overall risk reductions associated with glycemic control is greater for type 1 patients in DCCT than in type 2 patients in the UKPDS. For example, in the DCCT, the 1.9% difference in HbA1c between the intensive (9.1%) and conventional group (7.2%, a 21% reduction in HbA1c) was associated with a 63% reduction in retinopathy progression [3]. However, in the UKPDS, the 0.9% difference in HbA1c between the intensive (7.0%) and conventional group (7.9%, an 11% reduction) was associated with only a 21% reduction in retinopathy progression [4].

Recent epidemiological studies have added further evidence to the clinical trial findings. For example, a population-based cohort study of 339 patients with type 1 diabetes in Denmark showed that elevated HbA1c (p < 0.0001) and longer diabetes duration (p < 0.0001) were independent factors for the 6-year risk of retinopathy [102]. In fact, among patients with high HbA1c (10% or higher), retinopathy risk increased rapidly within a few years of developing diabetes, but in patients with low HbA1c (less than 6%), retinopathy risk remained low during the first 8 years of diabetes.

In summary, there is strong epidemiological and clinical trials evidence that intensive metabolic therapy maintaining near-normal glycosylated hemoglobin levels has a substantial long-term beneficial effect on the development of diabetic retinopathy and that this effect has no threshold and persists long after the initiation of such therapy. However, it is worth emphasizing that retinopathy risk appears not greatly affected in the short term by tight glycemic control, and that there is a lag of about 1½ to 2½ years between metabolic control and measureable changes to the risk of retinopathy.

Hypertension. A common comorbid condition in patients with diabetes is hypertension. The WESDR found that 17% of patients with type 1 diabetes at baseline had hypertension, and a further 25% developed hypertension after 10 years [103].

Hypertension has long been hypothesized to be a risk factor for retinopathy in patients with diabetes. Several mechanisms have been postulated to support this hypothesis. Impairment of retinal vascular autoregulation in response to elevated blood pressure may play a role, based on observations that diabetic patients with hypertension appear to have an impaired ability to regulate retinal blood flow when compared with nondiabetic patients [104]. Hypertension may also result in endothelial damage in the retinal vasculature [105], and an increase in expression of vascular endothelial growth factor and its receptors in diabetic patients [106]. Population-based studies show that, in nondiabetic adult patients, hypertension is strongly associated with presence of retinal hemorrhages and microaneurysms [55,56,58].

However, epidemiological studies in diabetic patients have provided inconsistent evidence regarding the relationship between hypertension and retinopathy development or progression, which has been demonstrated in some studies [8–10,15,83] but not others [12,20,99,102,107]. In the WESDR, higher blood pressure was associated with an increased 14-year incidence of diabetic retinopathy in younger-onset type 1 diabetes [83], independent of other risk factors such as baseline retinopathy status, glycosylated hemoglobin, and duration of diabetes. However, in older onset type 2 diabetes, neither systolic nor diastolic blood pressure was related to the 10-year incidence and progression of retinopathy [107]. No relationship between blood pressure and incident retinopathy was demonstrated in two other prospective studies of type 1 diabetes; the EURODIAB Study [99] and a Danish study of children and adolescents [102]. Other studies document an association between diabetic retinopathy severity with systolic, but not diastolic, blood pressure [14,17,45]. Associations also seem to be weaker among elderly type 2 patients [21,26]. The variability of these results may be related to inherent limitations in study design, selection bias in clinic-based studies, selective mortality in older patients with type 2 diabetes, lack of statistical adjustment for use of anti-hypertensive medications, and measurement errors in the assessment and definition of blood pressure and hypertension.

Clinical trial data, however, have provided much clearer and stronger evidence of the role of hypertension in retinopathy development and progression. In the UKPDS, 1048 patients with hypertension were randomized to a regimen of tight control (aiming for blood pressure less than 150/85 mmHg with atenolol or captopril) and less tight control (less than 180/105 mmHg) [5]. The group with tight blood pressure control had a 37% reduction in the risk of microvascular disease, a 34% reduction in the rate of progression of retinopathy by two or more steps using the modified ETDRS severity scale, and a 47% reduction in the deterioration of visual acuity by three lines or more using the ETDRS charts (for example, a reduction in vision from 20/30 to 20/60 or worse on a Snellen chart). In the tight control group, atenolol and captopril were equally effective in reducing the risk of developing these microvascular complications, suggesting that blood pressure reduction was more important than the type of medication used to reduce it. The effects of blood pressure control were independent of those of glycemic control. After 6 years of follow-up in the UKPDS, subjects with baseline blood pressure in the highest third of the study population (systolic blood pressure ≥ 140 mmHg)