The Wisconsin epidemiologic study of diabetic retinopathy: XVII

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII The 14-year Incidence and Progression of Diabetic Retinopathy and Associated Risk Factors in Type 1 Diabetes Ronald Klein, MD, Barbara E. K. Klein, MD, Scot E. Moss, MA, Karen J. Cruickshanks, PhD Objective: To examine the 14-year incidence and progression of diabetic retinopathy and macular edema and its relation to various risk factors. Design: Population-based incidence study. Setting: The study was conducted in an 11-county area in southern Wisconsin. Participants: Six hundred thirty-four insulin-taking persons with diabetes diagnosed before age 30 years participated in baseline, 4-year, 10-year, and 14-year follow-up examinations. Main Outcome Measures: The 14-year progression of retinopathy, progression to proliferative retinopathy, and incidence of macular edema were detected by masked grading of stereoscopic color fundus photographs using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Study retinopathy severity scheme. Results: The 14-year rate of progression of retinopathy was 86%, regression of retinopathy was 17%, progression to proliferative retinopathy was 37%, and incidence of macular edema was 26%. Progression of retinopathy was more likely with less severe retinopathy, being male, having higher glycosylated hemoglobin or diastolic blood pressure at baseline, an increase in the glycosylated hemoglobin level, and an increase in diastolic blood pressure level from the baseline to the 4-year follow-up. Increased risk of proliferative retinopathy or incidence of macular edema was associated with more severe baseline retinopathy, higher glycosylated hemoglobin at baseline, and an increase in the glycosylated hemoglobin between the baseline and 4-year follow-up examination. The increased risk of proliferative retinopathy was associated with the presence of hypertension at baseline, whereas the increased risk of a participant having macular edema develop was associated with the presence of gross proteinuria at baseline. Lower glycosylated hemoglobin at baseline was associated with improvement in retinopathy. Conclusions: These data suggest relatively high 14-year rates of progression of retinopathy and incidence of macular edema. These data also suggest that a reduction of hyperglycemia and hypertension may result in a beneficial decrease in the progression to proliferative retinopathy. Ophthalmology 1998;105:1801–1815

Originally received: November 18, 1997. Revision accepted: May 15, 1998. Manuscript no. 97768. From the Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin. Supported by National Institutes of Health grant EY03083 (RK, BEKK) and, in part, by Research to Prevent Blindness (RK, Senior Scientific Investigator Award). Glycosylated hemoglobin determinations were performed in the Core Laboratory of the Clinical Nutrition Center with support from U.S. Public Health Service grant P30AMAG 26659 (Earl Shrago, MD). Proprietary interest: none. Reprint requests to Ronald Klein, MD, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 610 North Walnut Street, 460 WARF, Madison, WI 53705-2397.

Diabetic retinopathy remains an important cause of loss of vision despite the use of intensive glycemic control and photocoagulation therapy.1– 6 Although a large number of epidemiologic studies have described the prevalence and incidence of diabetic retinopathy1,7–30 and its relationship to various characteristics, there have been few long-term cohort studies that have examined these relationships.31–36 In this report, we describe the 14-year progression of diabetic retinopathy, the incidence of proliferative retinopathy and macular edema, the changes in the progression of retinopathy, and the relationship of factors measured at baseline to the progression of retinopathy in a large population-based cohort of persons with type 1 diabetes mellitus.

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Ophthalmology Volume 105, Number 10, October 1998

Figure 1. Reasons for nonparticipation in the 14-year follow-up in the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

Materials and Methods Study Population The population, which has been described in previous reports,26 –28,36,37 consisted of a sample selected from 10,135 patients with diabetes who received primary care in an 11county area in southern Wisconsin from 1979 to 1980. This sample was composed of “younger-onset” persons and “olderonset” persons. These analyses will be limited to the group of younger-onset persons, all of whom were taking insulin and had been diagnosed before 30 years of age (n ⫽ 1210). There were 996 persons in this group who participated in the baseline examination (1980 –1982),26 891 in the 4-year follow-up,28 765 in the 10-year follow-up,36 and 634 in the 14-year follow-up. The reasons for nonparticipation and comparisons between participants and nonparticipants at baseline and the 4- and 10-year follow-ups have been presented elsewhere.26,28,36 For the 14-year follow-up, the reasons for nonparticipation are presented in Figure 1. Mean (⫾standard deviation) and median times between the baseline and 14-year follow-up examinations were 14.4 ⫾ 0.5 years and 14.3 years, respectively.

Procedures The baseline and follow-up examinations were performed in a mobile examination van in or near the city where the participants resided. All examinations followed a similar protocol that was approved by the institutional human subjects committee of the University of Wisconsin. The pertinent parts of the ocular and physical examinations included measuring weight, height, blood pressure,38 and intraocular pressure; dilating the pupils; taking stereoscopic color fundus photographs of seven standard fields39; performing a semiquantitative determination of glucose, ketone, and protein levels in the urine using Labstix (Ames, Elkhart, IN); and determining blood glucose and glycosylated hemoglobin A1 levels from a capillary blood sample.40,41 The normal range for glycosylated hemoglobin A1 was 4.6% to 7.9%. Its intra-assay coefficient of variation was 2.4%. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) glycosylated hemoglobin A1 microcolumn results compare with the Diabetes Control and Complications Trial (DCCT) glycosylated hemoglobin A1c results as follows: DCCT ⫽ 0.003 ⫹ 0.935 (WESDR).42 A structured interview was conducted by the examiners including questions about specific medications for control of hypergly-

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cemia and blood pressure and use of diuretic agents, the number of aspirin used during the 30 days before the baseline examination, and smoking history. If there was any question about medication usage, it was verified by a physician’s report.

Grading Protocol Grading protocols have been described in detail elsewhere28,43 and are modifications of the Early Treatment Diabetic Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of diabetic retinopathy.44,45 Interobserver and intraobserver variations and the validity of the systems have been evaluated, and the results have been presented elsewhere.28,43,45,46

Definitions For each eye, the maximum grade in any of the seven standard photographic fields was determined for each of the lesions and used in defining the “retinopathy levels” as follows36,45: Level 10: No retinopathy. Level 21: Microaneurysms (MAs) only or retinal hemorrhages (H) or soft exudates in the absence of MAs. Level 31: Microaneurysms and one or more of the following: venous loops 31 ␮m or greater; questionable soft exudate, intraretinal microvascular abnormalities (IRMA), or venous beading; and retinal H. Level 37: Microaneurysms and one or more of the following: hard exudate and soft exudate. Level 43: Microaneurysms and one or more of the following: H/MAs equaling or exceeding those in Standard Photo (SP) 1 in four or five fields; H/MAs equaling or exceeding those in SP 2A in one field; and IRMA in one to three fields. Level 47: Microaneurysms and one or more of the following: both IRMA and H/MA characteristics from level 43; IRMA in four or five fields; H/MAs equaling or exceeding those in SP 2A in two or three fields; and venous beading in one field. Level 53: Microaneurysms and one or more of the following: any two or three characteristics from level 47; H/MAs equaling or exceeding those in SP 2A in four or five fields; IRMA equaling or exceeding those in SP 8A; venous beading in two or more fields. Level 60: Fibrous proliferations only.

Klein et al 䡠 Fourteen-year Progression of Diabetic Retinopathy Level 61: No evidence of level 60 or 65 but scars of photocoagulation either in “scatter” or confluent patches, presumably directed at new vessels. Level 65: Proliferative diabetic retinopathy (PDR) less than Diabetic Retinopathy Study high-risk characteristics (DRSHRC). Lesions as follows: new vessels elsewhere (NVE); new vessels on or within 1 disc diameter (NVD) of the disc graded less than SP 10A; or preretinal (PRH) or vitreous hemorrhage (VH) less than 1 disc area (DA). Level 71: Diabetic Retinopathy Study high-risk characteristics (DRS-HRC). Lesions as follows: VH and/or PRH equaling or exceeding 1 DA; NVE equaling or exceeding half DA with VH and/or PRH; NVD less than SP 10A with VH or PRH or both; and NVD equaling or exceeding SP 10A. Level 75: Advanced PDR, lesions as follows: NVD equaling or exceeding SP 10A with VH or PRH or both. Level 85: End-stage PDR, lesions as follows: macula obscured by VH or PRH or both; retinal detachment at center of macula; phthisis bulbi; and enucleation secondary to complications of diabetic retinopathy. The retinopathy level for a participant was derived by concatenating the levels for the two eyes, giving the eye with the higher level greater weight. This scheme provided a 15-step scale (10/10, 21/⬍21, 21/21, 31/⬍31, 31/31, 37/⬍37, 37/37, 43/⬍43, 43/43, 47/⬍47, 47/47, 53/⬍53, 53/53, 60⫹/⬍60⫹, and 60⫹/60⫹) when all levels of proliferative retinopathy are grouped as 1 level. For purposes of classification, if the retinopathy severity could not be graded in an eye, it was considered to have a score equivalent to that in the other eye. The incidence of any retinopathy was estimated from all persons who had no retinopathy at the baseline examination (severity level 10/10) and who participated in the follow-up examinations. Progression to proliferative retinopathy was estimated from all persons who were free of this complication at the baseline examination. For persons with no or only nonproliferative retinopathy, progression was defined as the first instance of an increase in the severity of retinopathy by two steps or more from the baseline level at any of the follow-up examinations. Improvement in retinopathy was defined as the first instance of a two-step or more decrease in the severity of retinopathy from the baseline level at any follow-up examination. Progression and improvement were examined separately in persons who had proliferative retinopathy at the baseline examination because many of these individuals had received panretinal photocoagulation treatment. Macular edema was defined as thickening of the retina with or without partial loss of transparency within 1 disc diameter from the center of the macula6 or the presence of focal photocoagulation scars in the macular area associated with a history of development of macular edema as documented by stereoscopic fundus photographs. Clinically significant macular edema was based on the detailed gradings and was defined as the presence of any one of the following: retinal thickening at or within 500 ␮m of the center of the macula; and/or hard exudates at or within 500 ␮m of the center of the macula if associated with thickening of the adjacent retina; and/or a zone or zones of retinal thickening 1 disc area in size, at least part of which was within 1 disc diameter of the center.6 Whenever we found new signs of photocoagulation scars in the macular area in the absence of macular edema and we had not previously documented macular edema by grading fundus photographs taken at an earlier examination, we obtained fundus photographs from the participant’s ophthalmologist. In the absence of fundus photographs, we obtained medical records documenting that macular edema due to diabetes had been present before the focal (or grid) photocoagulation. In situations in which participants

gave a history of laser photocoagulation but there were no signs of treatment burns, we requested information from the treating ophthalmologist to verify that such treatment had been done and to ascertain whether macular edema had been present before focal laser treatment. If macular edema could not be graded in an eye, the individual was assigned the score of the other eye. The incidence of macular edema was estimated from data for all persons who had no macular edema and had not been treated previously with photocoagulation at the baseline examination and who had participated in at least one follow-up examination. Because clinically significant macular edema represents one category of macular edema, most of the analyses are focused on determining relationships between factors that could be modified (e.g., glycosylated hemoglobin) and the development of macular edema. Age was defined as the age at the time of the baseline examination in 1980 to 1982. Age at diagnosis of diabetes was defined as the age at the time the diagnosis was first recorded by a physician on the patient’s chart or in a hospital record. The duration of diabetes was that period between the age at diagnosis and the age at the baseline examination. Change in glycosylated hemoglobin is defined as the value at the 4-year examination minus the value at baseline. Change in blood pressure is defined as the value at 4-year examination minus the value at baseline. The means of both systolic and diastolic blood pressures were the averages of the last two of three measurements according to the protocol of the Hypertension Detection and Follow-up Program.38 Hypertension was defined as a mean systolic blood pressure of 160 mmHg or greater, and/or a mean diastolic blood pressure of 95 mmHg or greater, or a history of antihypertensive medication at the time of examination in individuals 25 years of age or older, or a mean systolic blood pressure of 140 mmHg or greater, and/or a mean diastolic blood pressure of 90 mmHg or greater, and/or a history of antihypertensive medication at the time of examination in younger persons. Cigarette smoking status was determined as follows: a person was classified as having never smoked if he/she had smoked fewer than 100 cigarettes in his/her lifetime; as being an exsmoker if he/she smoked more than this number of cigarettes in his/her lifetime but had stopped smoking before the examination; or as currently smoking if he/she had not stopped. For purposes of analysis, two dichotomous variables were defined: one to compare persons who formerly had smoked with those who had never smoked and one to compare persons who currently smoke with those who had never smoked. Pack-years smoked was calculated as the number of cigarettes smoked per day divided by 20, multiplied by the number of years of smoking from the time of diagnosis of diabetes. Proteinuria was defined as urine protein concentration of 0.30 g/l or greater as measured by Labstix (Ames, Elkhart, IN).

Statistical Methods Some participants who were observed at the 4-year or 10-year examinations and were still at risk of having an endpoint develop did not participate in the 14-year examination. Thus, these are censored observations. To compute cumulative 14-year rates while still using the information contained in these censored observations, the product–limit method was used.47 To test for trends in rates of incidence or progression and to compute relative risks, the methods of Mantel and Haenszel,48 stratified on the three follow-up periods, were used. The average annual incidence and progression rates between examinations were estimated from the formula: 1-(1-pn)1/n, where n is the number of years between examinations and pn is the n-year rate. Multivariable analyses were based on the discrete linear logistic model.49 We chose to use the

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Ophthalmology Volume 105, Number 10, October 1998 Table 1. Selected Baseline Characteristics of Participants and Nonparticipants in the 14-Year Follow-up Examination of the Wisconsin Epidemiologic Study of Diabetic Retinopathy Participants

Nonparticipants

Dead

Baseline Characteristic

N

Mean ⫾ SD

N

Mean ⫾ SD

P*

N

Mean ⫾ SD

P*

Age at diagnosis (yrs) Duration (yrs) Age (yrs) Glycosylated hemoglobin A1 (%)† Systolic BP (mmHg) Diastolic BP (mmHg) Body mass (kg/m2) Diabetic pack-years smoked‡ (yrs)

634 634 634

14.2 ⫾ 7.4 12.6 ⫾ 9.0 26.8 ⫾ 11.2

75 75 75

11.2 ⫾ 6.2 11.9 ⫾ 8.6 23.2 ⫾ 10.5

⬍0.001 0.56 ⬍0.01

56 56 56

17.3 ⫾ 7.8 20.4 ⫾ 12.2 37.7 ⫾ 14.6

⬍0.005 ⬍0.001 ⬍0.001

603 632 631 634 497

10.6 ⫾ 2.0 120 ⫾ 16 77 ⫾ 11 23.3 ⫾ 4.0 4.0 ⫾ 9.1

72 72 71 75 50

11.2 ⫾ 2.0 117 ⫾ 13 76 ⫾ 10 22.5 ⫾ 3.8 4.6 ⫾ 7.7

⬍0.05 0.09 0.44 0.09 0.64

54 56 56 55 52

11.8 ⫾ 2.5 136 ⫾ 23 83 ⫾ 12 24.1 ⫾ 5.1 13.1 ⫾ 22.5

⬍0.005 ⬍0.001 ⬍0.001 0.25 ⬍0.01

Sex (male) Proteinuria (present) Hypertension (present) No. of aspirin in last month‡ 0 1–29 ⱖ30 Smoking status‡ Non-smoker Ex-smoker Current smoker Visual acuity ⬎20/40 20/40–20/63 20/80–20/160 ⱕ20/200 Retinopathy None Mild nonproliferative Moderate nonproliferative Proliferative Panretinal photocoagulation (yes) Focal and/or grid photocoagulation (yes)

N

%

N

%

N

%

634 618 632

49.2 15.5 14.7

75 68 72

46.7 10.3 6.9

0.72 0.29 0.07

56 53 56

53.6 37.7 39.3

0.58 ⬍0.001 ⬍0.001

183 268 45

36.9 54.0 9.1

15 26 8

30.6 53.1 16.3

0.15

21 23 8

40.4 44.2 15.4

0.76

296 77 124

59.6 15.5 24.9

24 10 16

48.0 20.0 32.0

0.29

26 9 17

50.0 17.3 32.7

0.38

613 12 4 3

97.0 1.9 0.6 0.5

71 2 0 1

95.9 2.7 0.0 1.4

48 6 0 2

85.7 10.7 0.0 3.6

207 271 69 87 634 634

32.6 42.7 10.9 13.7 8.5 1.7

25 32 6 12 75 75

33.3 42.7 8.0 16.0 5.3 0.0

9 17 6 24 56 56

16.1 30.4 10.7 42.9 26.8 5.4

0.66

0.85 0.50 0.62

⬍0.001

⬍0.001 ⬍0.001 0.10

SD ⫽ standard deviation; BP ⫽ blood pressure. * For comparison with participants. † The WESDR HbA1 microcolumn results compare with the DCCT HbA1c results as follows: DCCT ⫽ 0.003 ⫹ 0.935 (WESDR).42 ‡ In persons ⱖ18 years of age.

person-specific approach of discrete linear logistic models and not methods for correlated observations such as generalized estimating equations for the following reasons. In situations in which covariates are systemic variables rather than eye-specific, the gain in power from using methods for correlated observations is minor. In our case, only one eye-specific variable, the baseline retinopathy level, is considered. In addition, little power is gained by using these methods when there is a high degree of correlation between eyes. This is the case in the current study. Finally, the personspecific approach chosen offers simplicity and ease of interpretation. Variables were selected in stepwise fashion. Continuous variables were used as such. The variables available for selection in all the models for the whole cohort were age, duration of diabetes, gender, glycosylated hemoglobin, change in glycosylated hemoglobin, systolic and diastolic blood pressure, change in systolic and diastolic blood pressure, hypertension, gross proteinuria, and severity of retinopathy at baseline. In addition, models including smoking history, pack-years smoked after diagnosis of diabetes, number of aspirin consumed in the 30 days before the baseline examination, and use of diuretics were run for those 18 years of

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age or older at baseline. For variables that are subject to change during the course of the study, models with time-varying covariates also were investigated.50

Results Characteristics of those who participated in the 14-year follow-up, those who did not participate because they could not be located or they refused, and those who had died in the 4-year interval between the 10- and 14-year examinations are given in Table 1. With the exception of older age at diagnosis, older age at the baseline examination, and lower glycosylated hemoglobin at the baseline examination, there were no significant differences in characteristics of those who participated compared to those who survived but did not participate. The 56 younger-onset persons who had died were older, had diabetes diagnosed at an older age, longer duration of diabetes, higher glycosylated hemoglobin, and higher systolic and diastolic blood pressures. They also were more likely to have

Klein et al 䡠 Fourteen-year Progression of Diabetic Retinopathy Table 2. Fourteen-Year Incidence of Any Retinopathy, Improvement or Progression of Retinopathy, Progression to PDR or HRC, or Incidence of Macular Edema or Clinically Significant Macular Edema by Sex Male No. at risk Incidence of any retinopathy (%) 95% CI No. at risk Improvement (%) 95% CI No. at risk Progression of retinopathy (%) 95% CI Progression to PDR (%) 95% CI Progression to PDR with HRC (%) 95% CI No. at risk Incidence of macular edema (%) 95% CI Incidence of CSME (%) 95% CI

Female

Total

142

119

261

97.7 94.6–100 184 12.6 7.7–17.5 354

94.0 89.3–98.7 200 20.5 14.6–26.4 358

95.9 93.2–98.6 384 16.8 12.9–20.7 712

91.6 88.5–94.7

79.8 75.3–84.3

85.6 82.9–88.3

37.5 32.0–43.0

36.1 30.8–41.4

36.8 33.1–40.5

16.3 12.2–20.4 342

10.3 7.0–13.6 346

13.3 10.6–16.0 688

29.7 24.4–35.0

22.6 17.9–27.3

26.1 22.6–29.6

21.2 16.5–25.9

12.8 9.1–16.5

17.0 14.1–19.9

PDR ⫽ proliferative diabetic retinopathy; PDR with HRC ⫽ proliferative diabetic retinopathy with high-risk characteristics for visual loss as defined in the Diabetic Retinopathy Study;5 CSME ⫽ clinically significant macular edema as defined in the Early Treatment Diabetic Retinopathy Study;6 CI ⫽ confidence interval.

had gross proteinuria, poorer visual acuity, more severe retinopathy, and panretinal photocoagulation at baseline than those who participated. The severities of retinopathy between eyes at all examinations were highly correlated. The Spearman correlation between the eyes was 0.91 at baseline, 0.91 at the 4-year follow-up, 0.90 at the 10-year follow-up, and 0.89 at the 14-year follow-up. All the correlation coefficients were statistically significant (P ⬍ 0.0001). The differences in severity of retinopathy of more than two steps between eyes varied across examinations from 3.8% to 5.5%. The 14-year incidence and rates of progression of retinopathy were high (Table 2). The percentage of improvement was higher and the percentages of progression of retinopathy and incidence of macular edema were lower for females than for males. Rates of progression to proliferative retinopathy were similar for males and females. By the 14-year examination, 36.8% (n ⫽ 238) of the cohort had proliferative retinopathy develop, 13.3% had DRSHRC develop, and 17.0% had clinically significant macular edema develop. In those with nonproliferative retinopathy (levels 21/21– 53/53) at the baseline examination, the 14-year rate of improving by two steps or more was 16.8% (n ⫽ 61) (Table 2). Because of the high incidence of retinopathy in the population (95.9%), we excluded this endpoint in all further analyses. The relationships between age and duration of diabetes at baseline and the 14-year improvement, progression, progression to proliferative retinopathy, or incidence of macular edema are presented in Tables 3 and 4. There was a significant (test of trend, P ⬍ 0.005) inverse relation between age at the baseline examination and progression of retinopathy. The highest rate of progression of retinopathy (94.2%) was in those 19 years of age or younger at

baseline, whereas the lowest rate (68.1%) was in those who were 35 years of age or older. Progression to PDR increased from 5.9% and the incidence of macular edema increased from 10.4% in those age 0 to 9 years to 42.7% and 31.1%, respectively, in those 35 years of age or older (test of trend, P ⬍ 0.001 and 0.005, respectively). Rates of improvement also increased with age at baseline (test of trend, P ⬍ 0.01). The 14-year rate of progression of retinopathy was inversely related (test of trend, P ⬍ 0.001), whereas that of progression of proliferative retinopathy was directly related to duration of diabetes (test of trend, P ⬍ 0.001). Persons with 10 or more years of diabetes at baseline were 1.97 (95% confidence interval [CI] 1.56, 2.50) and 1.33 (95% CI 0.99, 1.79) times as likely to have proliferative retinopathy and macular edema develop over the 14 years of follow-up, respectively, as those with fewer than 10 years’ duration of diabetes. Persons with longer duration of diabetes at baseline were more likely to improve than those with shorter durations of diabetes at baseline. After controlling for gender, severity of retinopathy, and glycosylated hemoglobin level at baseline, this relationship remained (data not shown). The relations of progression of retinopathy, progression to proliferative retinopathy, incidence of macular edema, and improvement of retinopathy were examined within age and duration groups (Table 4). After controlling for duration, progression of retinopathy and incidence of macular edema were associated with age at baseline. After controlling for age, progression to proliferative retinopathy was associated with duration of diabetes at baseline. There were no consistent trends for progression of diabetic retinopathy with increasing retinopathy severity at baseline (Table 5). Progression to proliferative retinopathy, progression to DRSHRC, and incidence of macular edema were significantly related (P ⬍ 0.001) to greater severity of retinopathy at baseline. In those with retinopathy severity level of 43/⬍43 (moderate nonproliferative retinopathy in at least one eye) or worse at baseline, the 14-year risk of having proliferative retinopathy develop was 67.7%; for DRS-HRC, it was 34.2%; and for macular edema, it was 34.4%. Of the 227 persons who were found to have proliferative retinopathy at baseline in at least 1 eye and the 92 with macular edema at baseline in at least 1 eye, 118 (52.0%) and 39 (42.4%), respectively, had died during the 14-year follow-up. In the 103 persons with DRS-HRC or worse in at least 1 eye, 68 (66%) had died by 14 years, significantly higher (P ⬍ 0.001) than in the 124 persons without DRS-HRC (40.3%, n ⫽ 50). Of the 91 persons with active proliferative retinopathy in at least 1 eye (level 65) at baseline who were re-examined, 28 (35.3%) were found to have proliferative retinopathy with at least DRS-HRC (levels 71 and 75) in at least 1 eye, and 6 (8.2%) were found to have progressed beyond DRS-HRC and to have lost vision in at least 1 eye (level 85) at the 14-year follow-up. New treatment was observed in 42 (46.2%) of this group. Of the 38 persons with DRS-HRC in at least 1 eye who were re-examined, 15 (47.0%) had progressed to level 85 in at least 1 eye and 4 (10.5%) in both eyes. New treatment was seen in 14 (36.8%). The estimates of the annual rate of progression, progression to proliferative retinopathy, and incidence of macular edema over the three study intervals are presented in Figure 2. The yearly estimates are similar for progression of diabetic retinopathy; however, there is an increase in the yearly estimated rates of progression to proliferative retinopathy from the first 4 years of the study to the following 6 years, which falls during the last 4 years of follow-up. Estimated annual incidence of macular edema was lowest in the last 4 years of follow-up. Glycosylated hemoglobin level at baseline was a significant predictor of progression of retinopathy, progression to proliferative retinopathy, and incidence of macular edema over the

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Ophthalmology Volume 105, Number 10, October 1998 Table 3. Fourteen-Year Improvement or Progression of Retinopathy, Progression to PDR, or Incidence of Macular Edema by Age or Duration of Diabetes at Baseline No. at Risk Age (yrs) 0–9 10–14 15–19 20–24 25–29 30–34 35⫹ P test of trend Duration (yrs) 0–2 3–4 5–9 10–14 15–19 20–24 25–29 30⫹ P test of trend

Improvement (%)

No. at Risk

Progression (%)

Progression to PDR (%)

Incidence of Macular Edema (%)

No. at Risk

0 5 57 83 68 58 113

— 20.0 10.5 12.1 12.2 14.9 28.0 ⬍0.01

27 80 140 130 101 102 132

93.7 93.5 95.1 87.0 89.0 78.8 68.1 ⬍0.005

5.9 22.2 37.6 40.3 41.7 38.2 42.7 ⬍0.001

24 77 137 127 94 99 130

10.4 18.7 22.6 26.4 29.3 30.4 31.1 ⬍0.005

5 5 94 112 68 41 32 27

40.0 20.0 9.6 9.0 14.8 21.5 43.2 41.7 ⬍0.001

75 84 229 140 79 42 34 29

86.6 91.2 92.1 90.3 80.5 59.4 65.3 48.5 ⬍0.001

14.9 17.7 36.9 56.6 41.7 35.3 46.2 24.2 ⬍0.001

72 81 224 124 74 44 35 34

12.9 19.3 29.2 33.1 24.1 33.7 27.0 16.7 0.07

PDR ⫽ proliferative diabetic retinopathy.

14-year period (Table 6). Progression of retinopathy, progression to proliferative retinopathy, and incidence of macular edema increased consistently from the lowest to the highest quartile of glycosylated hemoglobin level in all the comparisons. These findings were independent of duration of diabetes (Fig 3) or retinopathy severity at baseline (Fig 4). Within

each given quartile of glycosylated hemoglobin at baseline, progression to proliferative retinopathy (Fig 5) and incidence of macular edema (Fig 6) were higher in those whose glycosylated hemoglobin levels increased by 1.5% or more compared to those whose glycosylated hemoglobin levels decreased by 1.5% or more from the baseline to the 4-year follow-up. In

Table 4. Fourteen-Year Improvement of Retinopathy, Progression of Retinopathy, Progression to PDR, or Incidence of Macular Edema by Age and Duration of Diabetes at Baseline Duration (yrs) 0–4 Age (yrs) Improvement 0–19 20–29 30⫹ P† Progression of retinopathy 0–19 20–29 30⫹ P† Progression to proliferative diabetic retinopathy 0–19 20–29 30⫹ P† Incidence of macular edema 0–19 20–29 30⫹ P†

No. at Risk 7 2 1

5–9 % 28.6 50.0 0.0

29 46 19

15⫹

%

No. at Risk

%

No. at Risk

%

P*

6.9 13.0 5.3

24 61 27

8.3 6.6 14.8

2 42 124

50.0 17.0 28.6

0.12

95.6 89.4 88.5

35 72 33

100.0 90.1 81.1

4 45 135

100.0 78.6 63.8

0.97

32.7 43.4 36.8

35 72 33

56.4 51.6 68.8

4 45 135

50.0 47.4 35.2

⬍0.001

22.2 40.1 28.9

32 65 27

27.4 33.9 37.2

4 44 139

25.0 14.0 29.3

0.36

0.45 103 40 16

90.7 89.6 77.1

105 74 50 0.05

103 40 16

15.4 10.5 38.3

105 74 50 0.67

98 40 15

15.4 10.6 36.4

* P for duration controlling for age using the Mantel-Haenszel procedure. † P for age controlling for duration using the Mantel-Haenszel procedure.

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No. at Risk

10–14

104 72 48 0.03

Klein et al 䡠 Fourteen-year Progression of Diabetic Retinopathy Table 5. Fourteen-Year Incidence of Improvement or Progression of Retinopathy, Progression to PDR or HRC, and Incidence of Macular Edema by Retinopathy Level in the Worse Eye at Baseline Retinopathy Level in Worse Eye 10 21 31 37 43 47 53 60⫹ P test of trend

No. at Risk

Improvement (%)

No. at Risk

Progression (%)

Progression to PDR (%)

Progression to HRC (%)

— 89 74 125 52 32 12 —

— 3.7 9.1 20.1 31.8 26.0 37.5 — ⬍0.001

261 156 74 125 52 32 12 —

92.4 84.0 86.5 78.9 66.3 89.8 75.0 — 0.22

15.4 31.7 53.8 55.3 57.4 82.0 75.0 — ⬍0.001

5.0 11.1 20.0 14.1 25.1 42.7 53.3 — ⬍0.001

No. at Risk

Incidence of Macular Edema (%)

255 153 70 100 47 19 6 38

17.5 25.4 30.5 36.7 25.2 40.4 50.0 40.0 ⬍0.001

PDR ⫽ proliferative diabetic retinopathy; HRC ⫽ high-risk characteristics.

addition, after controlling for baseline retinopathy, duration of diabetes, and gender, each percentage point of lower glycosylated hemoglobin at baseline was associated with an increased odds of improvement of retinopathy (odds ratio 1.41; 95% CI 1.19, 1.67). Systolic blood pressure at baseline was related to progression to proliferative retinopathy, and diastolic blood pressure at baseline was related to progression of retinopathy, progression to proliferative retinopathy, and incidence of macular edema (Table 6). Hypertension at baseline was associated with a 91% increase in the risk of having proliferative retinopathy develop and a 40% increase in the risk of having macular edema develop. Gross proteinuria at baseline was associated with a 96% increase in the risk of having proliferative diabetic retinopathy develop and a 95% increase in the risk of having macular edema develop. Current users of diuretics at baseline had a 59% increased risk of progressing to proliferative retinopathy. In the WESDR, at the 10-year examination of those at risk of having PDR develop, of the 19 persons taking an angiotensin-converting enzyme (ACE) inhibitor at the time, the progression rate to PDR was 0.0% compared to 10.7% in the 374 not taking an ACE inhibitor (P ⫽ 0.13); for those at risk of having macular edema develop, of the 27 persons taking ACE inhibitors, the incidence of macular edema was 7.4% compared to 8.0% in the 377 persons not taking ACE inhibitors (P ⫽ 0.92). There was no relationship of smoking status to progression of retinopathy, progression to proliferative retinopathy, or to inci-

Figure 2. Estimated annual rates for three periods of the study.

dence of macular edema (Table 6). Use of aspirin at baseline was associated with a 68% increased risk of having macular edema develop. To evaluate the relative influence of several variables on the progression of retinopathy, progression to proliferative retinopathy, or incidence of macular edema, we developed models based on discrete linear logistic regression. These models are used to test the significance of variables in predicting an outcome when the effects of other variables are being considered. A list of possible variables to be selected is included in the Statistical Methods section. In all of the multivariable models, glycosylated hemoglobin level was a significant and independent predictor of progression, progression to proliferative retinopathy, and incidence of macular edema over the 14-year period (Tables 7–9). In the models, we also examined whether a change in glycemic control was associated with a change in the risk of progression of retinopathy while controlling for other characteristics in the models. The odds ratio for a 1-percentage-point increase in the glycosylated hemoglobin A1 level from baseline to the 4-year follow-up was 1.20 for progression of retinopathy, 1.33 for progression to proliferative retinopathy, and 1.32 for the incidence of macular edema. Furthermore, there was no evidence for a significant interaction between duration of diabetes and change in glycosylated hemoglobin. For instance, the odds ratio for a 1-percentage point increase in glycosylated hemoglobin was 1.21 at a duration of 5 years and 1.18 at a duration of 20 years for progression of retinopathy, 1.37 at 5 years and 1.21 at 20 years for progression to proliferative retinopathy, and 1.33 at 5 years and 1.28 at 20 years for incidence of macular edema. None of these interactions were statistically significant. In addition to glycosylated hemoglobin, higher diastolic blood pressure, less severe retinopathy at baseline, being male, and an increase in diastolic blood pressure were associated with an increased risk of progression of retinopathy (Table 7). Because of collinearity among baseline retinopathy level, age, and duration of diabetes, it is possible to include only one of these in the multivariate model. We chose to include retinopathy level. However, if retinopathy was not included, the odds ratio for a 10-year increment in age would be 0.83 with a 95% CI of 0.74, 0.92, and the odds ratio for a 10-year increment in duration of diabetes would be 0.75 with a 95% CI of 0.65, 0.88. More severe retinopathy and the presence of hypertension at baseline were associated with a increased risk of progression to proliferative retinopathy, and more severe retinopathy and the presence of gross proteinuria at baseline were associated with increased incidence of macular edema (Tables 8 and 9). Models also were developed with clinically signif-

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Ophthalmology Volume 105, Number 10, October 1998 Table 6. Fourteen-Year Progression of Retinopathy, Progression to Proliferative Retinopathy, and Incidence of Macular Edema by Various Characteristics at Baseline

Characteristic Sex Male Female Age at diagnosis (yrs) 0–9 10–19 20–29 Glycosylated hemoglobin A1 (%) 5.6–9.4 9.5–10.5 10.6–12.0 12.1–19.5 Systolic blood pressure (mmHg) 78–110 111–120 121–134 135–221 Diastolic blood pressure (mmHg) 42–71 72–78 79–85 86–117 Hypertension Absent Present Proteinuria Absent Present Diuretic use† Non-user Ex-user Current User Smoking history† Non-smoker Ex-smoker Current smoker Diabetic pack years smoked† 0 ⬍5 5–14 15⫹ No. of aspirin in last month† 0 1–29 30⫹

No. at Risk

Progression (%)

354 358

91.6 79.8

221 305 186

87.2 87.1 81.2

187 153 174 168

75.4 79.5 95.2 95.0

200 215 192 100

87.7 85.6 85.4 80.9

207 188 170 140

82.4 87.0 86.7 87.0

621 86

85.4 87.8

617 75

85.6 87.0

427 57 45

84.0 72.7 89.7

297 79 153

84.0 79.2 81.8

311 94 68 56

84.1 83.3 86.3 68.3

192 288 49

82.8 83.7 78.2

P*

RR (95% CI)

Progression to PDR (%)

P*

No. at Risk

Incidence of Macular Edema (%)

1.00 — 0.96 (0.76,1.22)

342 346

29.7 22.6

1.00 — 1.01 (0.77,1.33) 0.99 (0.72,1.34)

217 296 175

22.6 26.8 29.3

RR (95% CI)

P*

RR (95% CI)

⬍0.005 1.00 — 0.83 (0.73,0.93)

37.5 36.1

1.00 — 1.04 (0.91,1.19) 0.92 (0.79,1.08)

36.1 36.9 37.6

1.00 — ⬍0.001 1.37 (1.12,1.68) 1.99 (1.67,2.38) 2.64 (2.18,3.20)

13.1 34.8 45.6 58.6

1.00 — ⬍0.001 2.81 (1.77,4.47) 4.42 (2.90,6.72) 6.23 (4.21,9.22)

187 153 167 154

12.7 22.6 33.9 36.8

1.00 — 1.01 (0.86,1.17) 1.04 (0.89,1.22) 0.98 (0.80,1.20)

29.6 31.4 42.8 52.0

1.00 — ⬍0.001 1.12 (0.80,1.57) 1.56 (1.14,2.15) 2.06 (1.43,2.96)

199 201 178 106

25.9 23.9 21.6 38.8

1.00 — 1.13 (0.96,1.32) 1.17 (0.99,1.38) 1.20 (1.00,1.43)

25.7 34.5 40.5 52.8

1.00 — ⬍0.001 1.46 (1.03,2.06) 1.69 (1.20,2.39) 2.56 (1.82,3.58)

207 182 159 135

21.6 26.6 24.6 33.7

0.64

1.00 — 1.04 (0.87,1.26)

34.0 57.4

⬍0.001 1.00 — 1.91 (1.41,2.59)

596 88

25.1 31.1

0.65

1.00 — 1.05 (0.86,1.27)

34.6 57.7

⬍0.001 1.00 — 1.96 (1.43,2.68)

584 81

24.2 42.1

0.13

1.00 — 0.79 (0.62,1.00) 0.95 (0.73,1.22)

39.2 39.6 55.2

0.08

1.00 — 1.00 (0.66,1.50) 1.59 (1.06,2.40)

412 56 45

28.2 30.2 30.9

0.81

1.00 — 1.12 (0.68,1.84) 1.16 (0.66,2.05)

0.28

1.00 — 0.87 (0.71,1.08) 1.05 (0.90,1.24)

40.6 36.4 42.8

0.77

1.00 — 0.90 (0.62,1.32) 1.05 (0.79,1.40)

280 82 151

28.0 23.5 32.8

0.41

1.00 — 0.89 (0.54,1.44) 1.22 (0.86,1.74)

1.00 — 1.03 (0.86,1.25) 1.18 (0.96,1.45) 0.75 (0.58,0.98)

40.4 36.8 46.6 40.7

1.00 — 0.88 (0.62,1.25) 1.21 (0.83,1.76) 1.03 (0.66,1.60)

293 93 72 55

28.2 25.7 27.2 37.9

1.00 — 0.98 (0.85,1.14) 1.04 (0.81,1.35)

42.2 38.0 48.5

1.00 — 0.90 (0.68,1.18) 1.20 (0.77,1.85)

193 273 47

28.5 26.2 43.9

0.36

0.94

⬍0.05

0.34

0.89

0.76

0.93

0.63

0.88

0.08

0.15

1.00 — 0.77 (0.57,1.03) 1.00 — 1.23 (0.86,1.76) 1.34 (0.90,1.98)

1.00 — ⬍0.001 1.90 (1.12,3.25) 3.11 (1.95,4.95) 3.37 (2.12,5.34)

0.17

⬍0.05

0.11

1.00 — 0.94 (0.64,1.39) 0.86 (0.56,1.30) 1.58 (1.04,2.40)

1.00 — 1.30 (0.86,1.93) 1.16 (0.75,1.80) 1.76 (1.16,2.67) 1.00 — 1.40 (0.93,2.12)

⬍0.001 1.00 — 1.95 (1.34,2.82)

0.18

0.24

1.00 — 0.92 (0.58,1.43) 0.97 (0.58,1.61) 1.60 (1.00,2.58) 1.00 — 0.90 (0.64,1.28) 1.68 (1.03,2.74)

RR ⫽ relative risk; CI ⫽ confidence interval. * P values are based on the Mantel-Haenszel test of general association or the Mantel-Haenszel test of trend (age at diagnosis, glycosylated hemoglobin, systolic blood pressure, diastolic blood pressure, diabetic pack-years smoked, and number of aspirin in the last month). † Analyses restricted to those who were 18 years of age or older at baseline.

icant macular edema as an endpoint. The magnitude of the relationships as shown in Table 9 was similar except for gross proteinuria (data not shown). The multivariate analyses were repeated for persons 18 years of age or older to examine the relationship between smoking and use of aspirin and progression of retinopathy, progression to proliferative retinopathy, and incidence of macular edema. This restriction was added because younger subjects had very low-reported frequencies of exposure to these risk factors. For every 10 pack-years smoked after the diagnosis of diabetes, the risk of retinopathy

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progression decreased by 20% (OR 0.80; 95% CI 0.69, 0.94; P ⬍ 0.01) and the risk of progression to proliferative retinopathy decreased by 21% (OR 0.79; 95% CI 0.66, 0.95; P ⬍ 0.05). There was no relation of smoking to the incidence of macular edema. For those 18 years of age or older, those consuming 30 or more aspirin a month were 2.66 times as likely (95% CI 1.50, 4.72) to have macular edema develop compared to those who consumed less aspirin at baseline. When a history of cardiovascular disease was forced into the model, the relationship of aspirin to the incidence of macular edema remained. When age was forced into the models,

Klein et al 䡠 Fourteen-year Progression of Diabetic Retinopathy Gross proteinuria significantly entered the model (OR 1.65; 95% CI 1.03, 2.64), whereas hypertension was no longer a significant predictor for progression to proliferative retinopathy. Gross proteinuria was no longer a significant predictor of incidence of clinically significant macular edema (data not shown). The most common reason for nonparticipation in the follow-up examinations was death. If retinopathy progression was underreported in smokers because they were more likely to die, then the inverse association between smoking and retinopathy might be explained, in part, by this selective mortality. To investigate this possibility, we repeated the multivariate analyses using combined endpoints of progression of retinopathy or death and progression to proliferative retinopathy or death. These analyses showed that pack-years smoked was no longer related to progression of reti-

Figure 3. Fourteen-year (A) progression of retinopathy, (B) progression to proliferative retinopathy, and (C) incidence of macular edema by quartile of glycosylated hemoglobin and duration of diabetes as measured at baseline examination. Open circles indicate first quartile; solid diamonds indicate fourth quartile.

pack-years smoked was no longer related to progression of retinopathy (data not shown). To further examine the effect of changes in risk factors over the course of the study, models with time-varying covariates also were developed. For each interval in which a subject participated, the values of the risk factors at the beginning of the interval were used. In these models, glycosylated hemoglobin remained a significant predictor for progression of retinopathy, progression to proliferative retinopathy, and incidence of macular edema (data not shown). Diastolic blood pressure remained a significant predictor of progression of retinopathy (data not shown). Duration of diabetes (OR 0.75 per 10 years of diabetes; 95% CI 0.64, 0.87) significantly entered the model while retinopathy severity was no longer a significant predictor of progression of retinopathy. Severity of retinopathy remained a significant predictor of progression to proliferative retinopathy and macular edema (data not shown).

Figure 4. Fourteen-year (A) progression of retinopathy, (B) progression to proliferative retinopathy, and (C) incidence of macular edema by quartile of glycosylated hemoglobin and retinopathy severity in worse eye. Level 10, no retinopathy; level 21, minimal nonproliferative retinopathy; levels 31–37, moderate nonproliferative retinopathy; and levels 43–53, severe nonproliferative retinopathy at baseline.

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Ophthalmology Volume 105, Number 10, October 1998

Figure 5. Fourteen-year progression to proliferative retinopathy by glycosylated hemoglobin level at baseline and change in glycosylated hemoglobin level from the baseline to the 4-year follow-up of 1.5% points or more in the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

nopathy or progression to proliferative retinopathy (data not shown).

Discussion The data reported herein provide unique long-term population-based information regarding the incidence and progression of diabetic retinopathy and macular edema and its relationship to hyperglycemia, hypertension, and other factors. The cohort was composed of all known patients with type 1 diabetes diagnosed before 30 years of age who were receiving treatment in a defined geographic area during a specified period. The cohort was large, there was a broad distribution of severity of retinopathy at baseline, the follow-up intervals were defined and uniform for the cohort, there was a very low refusal rate, and loss of follow-up was most commonly because of death. The standardized protocols of measurement, including objective recording of diabetic retinopathy and macular edema using stereoscopic fundus photographs of seven standard fields, were consistent over time. The grading of fundus photographs was done in masked fashion using a standard classification system. The overall 14-year incidence of any retinopathy (96%), and rates of progression of retinopathy (86%), progression to proliferative retinopathy (37%), and incidence of macular edema (26%) were high. These findings are consistent with the few clinic- and population-based cohorts with longer follow-up to which these data can be compared. Based on our findings, we estimate that over a 14-year study period, of the 500,000 Americans with insulin-dependent diabetes,51 185,000 would have proliferative retinopathy develop, 65,000 would have proliferative retinopathy with DRSHRC develop, and 85,000 would have clinically significant macular edema develop. In addition, there appeared to be a decline in the estimated annual rates of progression to proliferative retinopathy and the incidence of macular edema in the last 4-year period of the study compared to earlier periods of the study. The reasons for this decline may

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involve better glycemic control during the study period52 or death leading to selection of the healthiest. This information is important in planning for counseling and rehabilitative services, projecting costs, measuring temporal trends, developing causal inferences, and providing sample size estimates for conducting clinical trials. For example, if there is a “true” annual decrease in the incidence of proliferative retinopathy and macular edema in persons with type 1 diabetes, there may be a need for fewer healthcare resources to detect and treat these individuals with panretinal and focal photocoagulation. The level of hyperglycemia, as measured by one glycosylated hemoglobin assessment at baseline, was found to be a strong and independent predictor of progression and improvement of retinopathy, progression to proliferative retinopathy, or incidence of macular edema over the 14-year period of the study. A 1-percentage-point decrease in the glycosylated hemoglobin level from baseline to 4-year follow-up would be expected to lead to a 25% decrease in the 14-year incidence of proliferative retinopathy and a 24% decrease in the 14-year incidence of macular edema in persons with type 1 diabetes. This confirmed our earlier findings at the 4- and 10-year follow-up examinations53–56 and is consistent with epidemiologic data from a number of other recent clinic- and population-based studies13,15–17,23,24,30,32,57 and from clinical trials.4,58 Our data also suggest that lower levels of glycosylated hemoglobin, even later in the course of diabetes or when moderate nonproliferative diabetic retinopathy is present, may modify the risk imposed by high levels of glycemia earlier. These findings are consistent with the findings of some4 but not other studies of persons with insulin-dependent diabetes mellitus (IDDM).59,60 Data from the DCCT show that in persons with IDDM, intensive glycemic control is associated with significant reduction in the progression and significant increase in improvement of established retinopathy independent of duration of diabetes and level of baseline retinopathy.61,62 However, data from that trial showed that the 9-year cumulative incidence of sustained three-step progression in persons with IDDM duration of 2.5 years or less

Figure 6. Fourteen-year incidence of macular edema by glycosylated hemoglobin level at baseline and change in glycosylated hemoglobin level from the baseline to the 4-year follow-up of 1.5% points or more in the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

Klein et al 䡠 Fourteen-year Progression of Diabetic Retinopathy Table 7. Discrete Linear Logistic Models, Progression of Retinopathy over the 14-Year Period* Characteristic Model 1 (whole cohort) Sex Glycosylated hemoglobin A1 Change in glycosylated hemoglobin A1 Diastolic blood pressure Change in diastolic blood pressure Baseline retinopathy (0–12 steps) Model 2 (in persons ⱖ18 yrs of age) Sex Glycosylated hemoglobin A1 Change in glycosylated hemoglobin A1 Diastolic blood pressure Change in diastolic blood pressure Baseline retinopathy (0–12 steps) Diabetic pack years smoked

Increment

P

OR

95% CI

Progression More Likely If:

Male 1% 1% 10 mmHg 10 mmHg 1 step

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.005

1.62 1.69 1.20 1.42 1.35 0.93

1.24, 2.12 1.53, 1.85 1.11, 1.30 1.21, 1.67 1.16, 1.57 0.89, 0.97

Male Higher Increase Higher Increase Less severe

Male 1% 1% 10 mmHg 10 mmHg 1 step 10 yrs

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.005 ⬍0.01 ⬍0.005 ⬍0.01

1.72 1.78 1.21 1.36 1.29 0.91 0.80

1.25, 2.36 1.58, 2.01 1.09, 1.34 1.12, 1.65 1.07, 1.56 0.86, 0.96 0.69, 0.94

Male Higher Increase Higher Increase Less severe Less

OR ⫽ odds ratio; CI ⫽ confidence interval. * None of the remaining variables achieved a statistical significance level of less than P ⫽ 0.28 with the exception of age and duration of diabetes.

without retinopathy at baseline was 7% compared to 20% in those with IDDM duration of more than 2.5 years in those treated with intensive therapy.63 In addition, the 9-year cumulative incidence of sustained three-step progression in the secondary intervention cohort was lower in eyes with retinopathy severity level 20/⬍20 to 35/⬍35 at baseline compared to eyes with retinopathy severity level 43/⬍43 or worse at baseline (11.5%–18.2% vs. 43.8%). These data suggested a benefit of beginning intensive treatment with insulin earlier in the course of diabetes before the onset of diabetic retinopathy. Diastolic blood pressure was found to be a predictor of progression of retinopathy and hypertension a predictor of progression to proliferative retinopathy in our cohort. In addition, we found that a 10-mmHg increase in diastolic blood pressure from baseline to the 4-year follow-up was associated with a 35% increase in the 14-year rate of progression. These findings were independent of glycosylated hemoglobin, age at examination, and severity of retinopathy at the baseline examination. Our findings are consistent with

earlier findings at the 10-year examination of a relationship of hypertension to increased risk of progression to proliferative retinopathy64 and to other studies of persons with type 1 diabetes.18,23,24,32 In addition, we previously had reported a significant relationship between systolic blood pressure and the incidence of diabetic retinopathy.65 We found no relationship between diuretics and progression of retinopathy or progression to proliferative retinopathy and incidence of macular edema. Recently, preliminary data from the Eurodiab Controlled Trial of Lisinopril in Insulin-dependent Diabetes Mellitus (EUCLID) study showed a 50% reduction in the progression of retinopathy, after adjustment for glycemic control, in nonhypertensive or mildly hypertensive persons in the Lisinopril treatment group compared to the placebo group.66 We did not have enough power to evaluate the relationship of use of ACE inhibitors to the progression of retinopathy, progression to PDR, or incidence of macular edema in our study. To date, with the exception of the EUCLID study, there are no data from completed controlled clinical trials showing the benefit

Table 8. Discrete Linear Logistic Models, Progression to Proliferative Diabetic Retinopathy over the 14-Year Period* Characteristic Model 1 (whole cohort) Baseline retinopathy (0–12 steps) Glycosylated hemoglobin A1 Change in glycosylated hemoglobin A1 Hypertension Model 2 (in persons ⱖ18 yrs of age) Baseline retinopathy (0–12 steps) Glycosylated hemoglobin A1 Change in glycosylated hemoglobin A1 Hypertension Diabetic pack-years smoked ⱖ30 aspirin/month

Increment

P

OR

95% CI

Proliferative Retinopathy More Likely If:

1 step 1%

⬍0.001 ⬍0.001

1.41 1.86

1.33, 1.50 1.67, 2.08

More severe Higher

1% Present

⬍0.001 ⬍0.005

1.33 2.12

1.21, 1.45 1.32, 3.40

Increase Present

1 step 1%

⬍0.001 ⬍0.001

1.38 1.81

1.29, 1.48 1.60, 2.05

More severe Higher

1% Present 10 yrs Yes

⬍0.001 ⬍0.05 ⬍0.05 0.06

1.29 1.88 0.79 1.80

1.16, 1.44 1.14, 3.11 0.66, 0.95 0.99, 3.29

Increase Present Less Taking

OR ⫽ odds ratio; CI ⫽ confidence interval. * None of the remaining variables achieved a statistical significance level of less than P ⫽ 0.19.

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Ophthalmology Volume 105, Number 10, October 1998 Table 9. Discrete Linear Logistic Models, Incidence of Macular Edema over the 14-Year Period* Characteristic Model 1 (whole cohort) Baseline retinopathy (0–14 steps) Glycosylated hemoglobin A1 Change in glycosylated hemoglobin A1 Proteinuria Model 2 (in persons ⱖ18 yrs of age) Baseline retinopathy (0–14 steps) Glycosylated hemoglobin A1 Change in glycosylated hemoglobin A1 Proteinuria ⱖ30 aspirin/month

Increment

P

OR

95% CI

Macular Edema More Likely If:

1 step 1%

⬍0.001 ⬍0.001

1.11 1.49

1.06, 1.16 1.34, 1.65

More severe Higher

1% Present

⬍0.001 ⬍0.05

1.32 1.69

1.20, 1.44 1.04, 2.75

Increase Present

1 step 1%

⬍0.005 ⬍0.001

1.08 1.48

1.02, 1.13 1.31, 1.67

More severe Higher

1% Present Yes

⬍0.001 0.06 ⬍0.001

1.30 1.66 2.66

1.16, 1.45 0.99, 2.78 1.50, 4.72

Increase Present Taking

OR ⫽ odds ratio; CI ⫽ confidence interval. * None of the remaining variables achieved a statistical significance level of less than P ⫽ 0.07.

of control of hypertension in reducing the risk of progression of retinopathy. Our data suggest such an effect, but we cannot assert that blood pressure control per se or any specific antihypertensive medication used to accomplish that end would lower risk. The presence of gross proteinuria at baseline in the WESDR was associated with a 96% increase in the risk of progression to PDR and a 95% increase in the risk of incidence of macular edema. However, after including other variables such as hypertension and glycosylated hemoglobin in the multivariate models, the relationship remained only for a higher risk of having macular edema develop. These findings are consistent with our earlier findings67 and with an increased nonsignificant risk in a younger, smaller cohort of persons with type 1 diabetes.57 In Steno (Denmark), persons with IDDM and gross proteinuria at baseline had an increased risk of progression to proliferative retinopathy (12% annually) compared to those without proteinuria (1%–2% annually).68 Aiello et al69 have reported that dialysis may reverse macular edema in some patients with diabetes with renal failure. The reasons for the relationships between gross proteinuria and the progression to proliferative retinopathy or the incidence of macular edema are not known. Alterations in prorenin, renin, and angiotensin, increased fibrinogen, and other unmeasured metabolic or rheologic changes related to diabetic renal disease have been shown to be associated with increased retinal ischemia, especially in eyes with no or minimal nonproliferative retinopathy.70,71 Our data confirm our previous findings and those from others of no relationship between cigarette smoking and the progression of diabetic retinopathy, progression to proliferative retinopathy, or incidence of macular edema.23,24,55,72,73 The weak protective effect of smoking on progression to proliferative retinopathy disappeared in the multivariate analyses after controlling for loss to follow-up owing to death. The strong established association between smoking and cancer and cardiovascular disease should be reason enough to advise against this behavior. The number of aspirin used in the 30 days before the baseline examination was associated with increased risk

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of having macular edema develop in persons with type 1 diabetes who were 18 years of age or older in our study. In the ETDRS, no relationship was found between the incidence of macular edema or loss of vision and aspirin use.74 The reasons for our findings are not known. It may be because of chance or as a result of unmeasured confounding. Our data confirm our earlier findings that progression to proliferative retinopathy and incidence of macular edema are associated with severity of baseline retinopathy.28,36,55 In the WESDR population of persons with IDDM, the 14-year rate of progression to proliferative retinopathy varied from 15% in those with no retinopathy at baseline to 82% in those with moderately severe nonproliferative retinopathy (level 47 in either eye) at baseline; for the incidence of macular edema, the rates varied from 17.5% in those with no retinopathy to 40% in those with level 47 in either eye. These rates are lower than those reported in the Diabetic Retinopathy Study5 and the ETDRS.45 Our data suggest that even persons with no retinopathy at baseline are in need of ophthalmologic observation because of the significant number at risk of progressing to proliferative retinopathy during the 14 years of follow-up. In addition, persons with less-severe retinopathy are at higher risk of progression of retinopathy (as defined by the ETDRS severity scale) than those with more severe retinopathy. This may be a result of the ordinal nature of the scale (inequality of its steps), with two or more steps of progression at the lower end of the retinopathy severity scale having less change than two or more steps at the upper end of the scale. Through the first 10 years of follow-up, no one who was younger than 10 years of age at baseline had progressed to proliferative disease. However, at the 14-year follow-up, 6% had progressed to proliferative disease and 10% had macular edema develop. These rates still are significantly (P ⬍ 0.001) lower than in those who were 10 years of age or older at baseline, even though the former group had all passed through puberty after 14 years of follow-up. These results are consistent with observations from a number of other studies suggesting

Klein et al 䡠 Fourteen-year Progression of Diabetic Retinopathy there is a relative “protective” effect in the years before puberty in children with diabetes.75,76 These results also suggest that this advantage may remain for a time after puberty. These findings confirm current guidelines for ophthalmologic care for persons with diabetes.77 Ophthalmologic care for detection of vision-threatening retinopathy is not indicated in persons who are younger than 12 years because proliferative retinopathy and macular edema are rare in that age group. Thereafter, persons with diabetes should be under ophthalmologic observation depending on the duration of diabetes, severity of retinopathy found, and methods used to detect retinopathy.1 In univariate analyses, persons with longer duration of diabetes at baseline were more likely to improve than those with shorter durations of diabetes. This relation was not explained by level of glycemic control or retinopathy severity at baseline. The reason for this finding is not known. It may be because of residual confounding with baseline retinopathy level. There also could be some unmeasured confounding. Early in the disease when minimal retinopathy is present, risk factors present favor progression. However, after 10 to 15 years of diabetes, the process starts to “slow down.” Although many patients may have reached the most severe levels of retinopathy, some, who have not had proliferative retinopathy develop, begin to improve. Caution should be observed when interpreting the findings from our study. Mortality may affect the relation of risk factor to incidence of endpoints in our study. Because glycosylated hemoglobin, blood pressure, gross proteinuria, and retinopathy severity level are significantly associated with both incidence of macular edema and/or progression to proliferative retinopathy and decreased survival,78 it is likely that the effect of death would be to diminish the strength of these relationships. We do not expect that an important bias results from nonparticipation in follow-up examinations in those who had not died as there were few differences between them and participants. In addition, the estimates between change in the glycosylated hemoglobin and diastolic blood pressure over the first 4 years of the study and 14-year rates of progression of retinopathy may be affected by measurement error and regression to the mean. However, the changes observed are large enough to give us confidence that they reflect actual changes in the population. In summary, our data suggest that better glycemic control at any level of hyperglycemia and at any time during the course of diabetes, and control of blood pressure may be beneficial in reducing the incidence of macular edema or the progression to proliferative retinopathy or both. In addition, our data confirm the current guidelines for ophthalmologic care for detecting proliferative retinopathy and clinically significant macular edema over the long-term course of diabetes. Acknowledgment. The authors thank the 452 Wisconsin physicians and their staffs who participated in and supported this study. The authors also thank Richard J. Chappell, PhD, Dayna S. Dalton, MPH, Matthew D. Davis, MD, Stacy M. Meuer, BA, Moneen Meuer, BA, Polly A. Newcomb, PhD, Mari Palta, PhD, and Kathy Peterson, RN, for their assistance; the local hospitals that provided supportive services for the

mobile van; and the State of Wisconsin Division of Health for donating the van.

References 1. Klein R, Klein BEK. Vision disorders in diabetes. In: Diabetes in America. National Diabetes Data Group. 2nd ed. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 1995;293–338. (NIH publication; no. 951468). 2. Tielsch JM. Vision Problems in the U.S. Schaumburg, IL: Prevent Blindness America, 1994;1–20. 3. Moss SE, Klein R, Klein BEK. Ten-year incidence of visual loss in a diabetic population. Ophthalmology 1994;101:1061– 70. 4. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329: 977– 86. 5. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology 1981; 88:583– 600. 6. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796 – 806. 7. Dorf A, Ballintine EJ, Bennett PH, Miller M. Retinopathy in Pima Indians. Relationships to glucose level, duration of diabetes, age at diagnosis of diabetes, and age at examination in a population with a high prevalence of diabetes mellitus. Diabetes 1976;25:554 – 60. 8. Bennett PH, Rushforth NB, Miller M, LeCompte PM. Epidemiologic studies of diabetes in the Pima Indians. Recent Prog Horm Res 1976;32:333–76. 9. Kahn HA, Leibowitz HM, Ganley JP, et al. The Framingham Eye Study. I. Outline and major prevalence findings. Am J Epidemiol 1977;106:17–32. 10. West KM, Erdreich LJ, Strober JA. A detailed study of risk factors for retinopathy and nephropathy in diabetes. Diabetes 1980;29:501– 8. 11. King H, Balkau B, Zimmet P, et al. Diabetic retinopathy in Nauruans. Am J Epidemiol 1983;117:659 – 67. 12. Ballard DJ, Melton LJ III, Dwyer MS, et al. Risk factors for diabetic retinopathy: a population-based study in Rochester, Minnesota. Diabetes Care 1986;9:334 – 42. 13. Danielsen R, Jonasson F, Helgason T. Prevalence of retinopathy and proteinuria in type 1 diabetics in Iceland. Acta Med Scand 1982;212:277– 80. 14. Constable IJ, Knuiman MW, Welborn TA, et al. Assessing the risk of diabetic retinopathy. Am J Ophthalmol 1984;97:53– 61. 15. Knuiman MW, Welborn TA, McCann VJ, et al. Prevalence of diabetic complications in relation to risk factors. Diabetes 1986;35:1332–9. 16. Sjolie AK. Ocular complications in insulin treated diabetes mellitus. An epidemiological study. Acta Ophthalmol Suppl 1985;172:1–77. 17. Nielsen NV. Diabetic retinopathy I. The course of retinopathy in insulin-treated diabetics. A one year epidemiological cohort

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35. Lee ET, Lee VS, Kingsley RM, et al. Diabetic retinopathy in Oklahoma Indians with NIDDM. Incidence and risk factors. Diabetes Care 1992;15:1620 –7. 36. Klein R, Klein BEK, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol 1994;112:1217–28. 37. Klein R, Klein BEK, Moss SE, et al. Prevalence of diabetes mellitus in southern Wisconsin. Am J Epidemiol 1984;119: 54 – 61. 38. The hypertension detection and follow-up program. Hypertension Detection and Follow-Up Program Cooperative Group. Prev Med 1976;5:207–15. 39. Early Treatment Diabetic Retinopathy Study (ETDRS). Manual of Operations. 1985; Chapters 12, 18. Available from: National Technical Information Service (Accession #PB85223006). 40. Quick-Step, Fast Hemoglobin Test System. Akron, OH: Isolab, 1981;1– 8. 41. Moss SE, Klein R, Klein BEK, et al. Methodologic considerations in measuring glycosylated hemoglobin in epidemiologic studies. J Clin Epidemiol 1988;41:645–9. 42. DCCT Research Group, Klein R, Moss S. A comparison of the study populations in the Diabetes Control and Complications Trial and the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch Intern Med 1995;155:745–54. 43. Klein R, Klein BEK, Magli YL, et al. An alternative method of grading diabetic retinopathy. Ophthalmology 1986; 93:1183–7. 44. Grading diabetic retinopathy from stereoscopic color fundus photographs — an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98(5 Suppl):786 – 806. 45. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS Report number 12. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98:823–33. 46. Klein BEK, Davis MD, Segal P, et al. Diabetic retinopathy. Assessment of severity and progression. Ophthalmology 1984;91:10 –7. 47. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 81. 48. Mantel N. Chi-square tests with one degree of freedom: extensions of the Mantel–Haenszel procedure. J Am Stat Assoc 1963;58:690 –700. 49. Hosmer DW Jr, Lemeshow S. Applied Logistic Regression. New York: Wiley, 1989;238 – 45 (Wiley series in probability and mathematical statistics). 50. Parmar MKB, Machin D. Survival Analysis: A Practical Approach. New York: Chichester; J. Wiley, 1995;160 –77. 51. LaPorte RE, Matsushima M, Chang Y-F. Prevalence and incidence of insulin-dependent diabetes. In: Diabetes in America. National Diabetes Data Group. 2nd ed. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1995;37– 46 (NIH publication; no. 95-1468). 52. Klein R, Klein BEK, Moss SE, Cruickshanks KJ. The medical management of hyperglycemia over a 10-year period in people with diabetes. Diabetes Care 1996;19:744 –50. 53. Klein R, Klein BEK, Moss SE, et al. Glycosylated homoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 1988;260:2864 –71. 54. Klein R, Klein BEK, Moss SE, Cruickshanks KJ. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med 1994;154:2169 –78.

Klein et al 䡠 Fourteen-year Progression of Diabetic Retinopathy 55. Klein R, Klein BEK, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology 1984;91:1464 –74. 56. Klein R, Moss SE, Klein BEK, et al. The Wisconsin epidemiologic study of diabetic retinopathy. XI. The incidence of macular edema. Ophthalmology 1989;96:1501–10. 57. Vitale S, Maguire MG, Murphy RP, et al. Clinically significant macular edema in Type I diabetes. Incidence and risk factors. Ophthalmology 1995;102:1170 – 6. 58. Reichard P, Nilsson BY, Rosenqvist U. The effect of longterm intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993;329:304 –9. 59. Warram JH, Manson JE, Krolewski AS. Glycosylated hemoglobin and the risk of retinopathy in insulin-dependent diabetes mellitus [letter]. N Engl J Med 1995;332:1305– 6. 60. Danne T, Weber B, Hartmann R, et al. Long-term glycemic control has a nonlinear association to the frequency of background retinopathy in adolescents with diabetes. Follow-up of the Berlin Retinopathy Study. Diabetes Care 1994; 17:1390 – 6. 61. The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes 1996;45:1289 –98. 62. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial. Arch Ophthalmol 1995;113:36 –51. 63. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995;102:647– 6. 64. Klein BEK, Klein R, Moss SE, Palta M. A cohort study of the relationship of diabetic retinopathy to blood pressure. Arch Ophthalmol 1995;113:601– 6. 65. Klein R, Klein BEK, Moss SE, et al. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Arch Intern Med 1989;149:2427–32. 66. Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998;351:28 –31.

67. Klein R, Moss SE, Klein BEK. Is gross proteinuria a risk factor for the incidence of proliferative diabetic retinopathy? Ophthalmology 1993;100:1140 – 6. 68. Kofoed–Enevoldsen A, Jensen T, Borch–Johnsen K, Deckert T. Incidence of retinopathy in type I (insulin-dependent) diabetes: association with clinical nephropathy. J Diabet Complications 1987;1:96 –9. 69. Aiello LM, Rand LI, Briones JC, et al. Nonocular clinical risk factors in the progression of diabetic retinopathy. In: Little HL, Jack RL, Patz A, Forsham PH, eds. Diabetic Retinopathy. New York: Thieme–Stratton; Stuttgart; New York: G. Thieme Verlas, 1983. 70. Borch–Johnsen K, Kreiner S. Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987;294:1651– 4. 71. Winocour PH, Durrington PN, Ishola M, et al. Influence of proteinuria on vascular disease, blood pressure, and lipoproteins in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987;294:1648 –51. 72. Moss SE, Klein R, Klein BEK. Association of cigarette smoking with diabetic retinopathy. Diabetes Care 1991;14:119 –26. 73. Moss SE, Klein R, Klein BEK. Cigarette smoking and tenyear progression of diabetic retinopathy. Ophthalmology 1996;103:1438 – 42. 74. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98(5 Suppl):757– 65. 75. Murphy RP, Nanda M, Plotnick L, et al. The relationship of puberty to diabetic retinopathy. Arch Ophthalmol 1990;108: 215– 8. 76. Kostraba JN, Dorman JS, Orchard TJ, et al. Contribution of diabetes duration before puberty to development of microvascular complications in IDDM subjects. Diabetes Care 1989; 12:686 –93. 77. Screening guidelines for diabetic retinopathy. American College of Physicians, American Diabetes Association, and American Academy of Ophthalmology. Ann Intern Med 1992; 116:683–5. 78. Klein R, Moss SE, Klein BEK, DeMets DL. Relation of ocular and systemic factors to survival in diabetes. Arch Intern Med 1989;149:266 –72.

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