Relationship of Duration and Onset of Diabetes toPrevalence of Diabetic Retinopathy

Bengt Jerneld, M.D., and Peep AIgvere, M.D.

In a population study of all registeredinsulin-treated diabetic patients on theSwedish island of Gotland, the prevalence ofdiabetic retinopathy was determined withophthalmoscopy, biomicroscopy, and colorphotography. Retinopathy was present in 173of 368 patients (470/"...) and reached a prevalenceof 100% after 30 years of diabetes. Proliferativeretinopathy was found in 48 subjects (13%)and was more common in females (17%) thanin males (9.4%) (P = .01). By simple logisticregression test, the prevalence of total andproliferative retinopathy was correlated withboth duration and age at onset of diabetes (P <.00l). However, on multiple regression analy­sis only the relationship with duration wasstatistically significant (P < .001); age at onsetwas not (P > .2). Age had an additional influ­ence only on background retinopathy withhard exudates, which were more frequent inolder subjects (P < .01). Thus, age at onset ofdiabetes was not correlated with the preva­lence of total or proliferative retinopathy.

POPULATION STUDIES indicate that the preva­lence of diabetic retinopathy varies between24% and 70% in different countries.!" In Swe­den, the prevalence of retinopathy in patientswith insulin-treated diabetes 40 years of age oryounger was found to be 66%9; in orally treateddiabetic patients of all ages it was 17%.10

The aim of this study was to determine theprevalence of retinopathy among insulin­treated diabetic patients in a well-defined and

Accepted for publication June 25, 1986.From the Department of Ophthalmology, Karolinska

Institute and Hospital, Stockholm, Sweden. This studywas supported by grants from the Clas GroschinskyMemorial Foundation, the Carmen and Berti! RegnerFoundation, and Praktikertjanst, Inc., Stockholm, Swe­den.

Reprint requests to Bengt [erneld, M.D., Departmentof Ophthalmology, Karolinska Hospital, Box 60500,10401 Stockholm, Sweden.

stable population. The area selected was theSwedish island of Gotland. From these data,which included all insulin-treated diabetic pa­tients registered by census in this municipalarea, it was possible to study the relationshipof prevalence to the duration of diabetes and toage at onset in various age groups. Since thesetwo variables may influence each other, weused multiple logistic regression analysis.

SUbjects and Methods

Subjects-The study included 399 registeredinsulin-treated diabetic patients who were reg­istered as permanent residents on the Swedishisland of Gotland. The total population was55,623 (December 1981), and thus the preva­lence of insulin-treated diabetes was 0.72%,which is the average for Sweden. 11 The numberof diabetic patients was checked with the. rec­cords at the only Department of Internal Medi­cine (Visby County Hospital) and with theprescriptions for antidiabetic drugs received bythe five pharmacies on the island during asix-month period in 1981. A six-month list ofinsulin prescriptions is sufficient to traceinsulin-treated diabetic patients in a popula­tiori."

Fourteen of the patients were children underthe age of 15 years. All had normal ophthalmo­scopic findings and they were not included inthe study. Ten patients died before examina­tion, and six refused to participate. One subjecthad bilateral dense cataracts, and ultrasonog­raphy could not be performed. All nonpartici­pants (mean age, 75 years; mean duration ofdiabetes, 8.0 years) had adult-onset diabetes.

Figure 1 shows the age distribution of the 368participating patients (181 men and 187women) (mean age, ± S.D., 55 ± 19.2 years).Figure 2 shows the duration of diabetes (meanduration, 13 ± 9.5 years), and Figure 3 showsage at diagnosis. For comparison with otherstudies,S,13-l6 we divided the patients into two

©AMERICAN JOURNAL OF OPHTHALMOLOGY 102:431-437, OCTOBER, 1986 431

432 AMERICAN JOURNAL OF OPHTHALMOLOGY October, 1986

20

o 10 20 30 40 50 60 70 80 soAge at examination

Fig. 1 (Jerneld and Algvere). Distribution of age atexamination. The peak is at 60 to 75 years.

groups by age at onset of diabetes. The"younger" group of 171 subjects (onset of dia­betes at 40 years of age or earlier) had a meanage of 38 ± 12.5 years (range, 15 to 64 years)and a mean duration of disease of 17 ± 11.2years (range, one to 50 years). The "older"group of 197 patients (onset of diabetes afterthe age of 40 years) had a mean age of 69 ± 9.6years (range, 44 to 93 years) and a mean dura­tion of disease of 11 ± 6.6 years (range, one to29 years).

Methods-After dilation of their pupils withtropicamide 1% and phenylepinephrine 10%,the patients underwent ophthalmoscopy andbiomicroscopy with the Goldmann three­mirror lens. Fundus photography was per­formed as recommended by the Diabetic Reti­nopathy Research Croup." modified to suit a45-degree fundus camera. We photographedseven areas of the fundus and projected thecolor slides onto a screen (magnification, x 8)for assessment, in a masked fashion, by twoindependent observers. All findings were re­corded and fed into a computer for evaluation.The patients were classified according to themost severe changes found by any method inthe worst eye. The fundus changes were divid­ed into three categories: (1) Background retinopa-

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thy, defined as the presence of one or more ofthe following signs: microaneurysms, punctateor striate intraretinal hemorrhages, hard exu­dates, and fewer than five soft exudates. Therewere two subgroups-those with and thosewithout hard exudates. (2) Preproliferative reti­nopathy, defined as five or more cotton-woolspots, venous beading, and intraretinal micro­vascular abnormalities.P-" (3) Proliferative reti­nopathy, subdivided into neovascularization onor within 1 disk diameter of the optic disk areain extent and neovascularization elsewhere inthe retina. 20,21

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Vol. 102, No.4 Diabetic Retinopathy 433

Results

Diabetic retinopathy was present in 173 ofthe 368 patients examined (47%). Backgroundretinopathy was present in 112 subjects (31%),preproliferative retinopathy in 13 (3.5%), andproliferative retinopathy in 48 (13%).

The prevalence of retinopathy varied consid­erably between groups of different ages atonset of diabetes (P < .001). The highest preva­lence (62%) was found among patients withonset at 20 or less years of age, and the lowest(21%) when diabetes was diagnosed after theage of 60 years (P < .001). The difference in theprevalence of proliferative retinopathy be­tween patients with early (20 or less years ofage) and late (more than 60 years of age) onsetwas even larger, 28% vs 5% (P < .001) (Table 1).

Subjects with onset of diabetes at 40 or lessyears of age had a significantly higher preva­lence of total retinopathy (56%) and of prolifer­ative retinopathy (18%) than patients with lateronset (40% and 8.1%, respectively). With long­er duration of diabetes there was a gradualincrease in the prevalence of both total retinop­athy (P < .001) and proliferative retinopathy(P < .001) (Fig. 4).

There was a correlation between age at onsetand duration of diabetes (r = -0.44; P < .001).This required a multiple logistic regressionanalysis which, again, showed that the dura­tion of diabetes was significantly correlated tototal (P < .001) and proliferative (P < .001)retinopathy. However, multiple logistic regres­sion analysis did not correlate the age at onsetof diabetes to total retinopathy (P > .2) or toproliferative retinopathy (P > .2) when dura­tion was taken into account. The difference inthe prevalence of retinopathy between thegroups of different ages at onset thus resultedfrom differences in the duration of diabetes,and age had no significant influence on reti­nopathy (Table 1).

There was an increasing prevalence of reti­nopathy with longer duration of diabetes in allfour age groups at onset of diabetes (Fig. 5).This was particularly notable for proliferativeretinopathy in all but the oldest age group(more than 60 years of age). The increase wasmost pronounced in patients with early onsetof diabetes (20 or less years of age), in whom

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20

diabetic complications were assigned to thecategory of proliferative retinopathy. Eyes withpreretinal or intravitreal hemorrhages wereclassified according to their other funduschanges, except when combined with neovas­cularization on the optic disk of less than 25%of the optic disk diameter, which put them inGroup 3 according to Diabetic RetinopathyStudy." Eyes with media opacities that pre­cluded inspection of the fundus were examinedby A- and B-scan ultrasonography. The ultra­sonographic findings were categorized as vitre­ous bleeding or membranes, prepapillary pro­liferations, and retinal detachment.P Vitreoushemorrhages and membranes were classified asbackground retinopathy, and prepapillary orpreretinal proliferations or retinal detachmentas proliferative retinopathy. Eight eyes (of fivepatients) with photocoagulation scars wereclassified according to their current status.

The statistical evaluation was based on sim­ple and multiple logistic regression analysis"with a variable indicating the presence or ab­sence of retinopathy as the dependent variable,and age at examination, age at onset of diabe­tes, duration, and sex as the independent vari­ables. In the logistic analysis, we used theindependent variables with their numeric val­ues; in the illustrations and tables they wereclassified. The P values obtained from the logis-

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434 AMERICAN JOURNAL OF OPHTHALMOLOGY October, 1986

Duration (years)Fig. 4 (Jerneld and Algvere). Prevalence of retinop­

athy and duration of diabetes. Solid bars show prolif­erative retinopathy. After 30 years, retinopathy wasfound in 100% of patients and proliferative retinopa­thy in 65%; n, number of subjects in each durationgroup.

the prevalence of proliferative retinopathyreached 55% after a duration of more than 20years. In subjects with onset of diabetes be­tween 41 and 60 years, this prevalence was 38%but the difference was not statistically signifi­cant (P>.05). Within the three groups ofpatients with different durations of diabetes,

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there was no significant change in the preva­lence of retinopathy with increasing age atonset of diabetes (Fig. 5). The higher preva­lence of retinopathy in those with durations ofzero to ten years and with the onset of diabetesat 41 to 60 years could have resulted fromchance.

There was no significant sex difference in theprevalence of total retinopathy. However, pro­liferative retinopathy was present in 31 of 187women (17%) and 17 of 181 men (9.4%) (P <.05), and this difference became even moresignificant when the duration was consideredin the analysis (P = .01).

Hard exudates were found in 87 patients(24%). The prevalence of hard exudates wasclearly related to the duration of diabetes (P <.001), and increased conspicuously after a du­ration of ten years (Table 2). There was no sexdifference. In contrast to total retinopathy, inpatients with hard exudates at examination ageprovided statistically significant additional in­formation (P < .01). In the total group, age wasnot correlated to the duration of diabetes (r =

0.01), and a simple listing of the various agegroups therefore yielded a correct estimate ofthe additional (predictive) value of the age atexamination when the duration was given(Table 2). In subjects with retinopathy, the ratiobetween those with and those without hardexudates was 1:2 when diabetes was diagnosedat 20 or less years of age but 2:1 when diabeteswas diagnosed after the age of 60 years.

Generally, the status of the fundus in felloweyes was in good accordance. In 311 of 350subjects (89%) both eyes of each individual hadthe same retinal status; the inclusion of thosewith a difference of one degree in severity ofretinopathy increased this to 335 of 350 patients(96%).

TABLE 1PREVALENCE OF RETINOPATHY, AGE AT ONSET, AND DURATION OF DIABETES

NO. WITH RETINOPATHY BY AGE AT ONSET (YRS)

DURATION OF DIABETES (YRS) "'20 21 to 40 41 to 60 «61 T,OTAL (%)

o to 5 1 of 13 2 of 20 4 of 22 3 of 29 12

6 to 10 3 of 13 4 of 20 12 of 30 3 of 22 26

11 to 15 4 of 8 6 of 11 15 of 31 6 of 21 44

16 to 20 6 of 9 13 of 16 17 of 22 2 of 2 78

21 or more 39 of 42 17 of 19 15 of 16 1 of 2 91

Mean (± S.D.) duration 19.7 ±12.5 13.6 ± 8.8 12.5 ± 7.0 7.7 ± 4.8 13.4 ± 9.5

Prevalence (%)

Total retinopathy 62 49 52 21 47

Proliferative retinopathy 28 9 10 5 13

Vol. 102, No.4

Age0-20

at onset21-40 41-60

Diabetic Retinopathy

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In 394 normal eyes, the fellow eye was nor­mal in 378 (96%) and proliferative retinopathywas present in four (1%). The probability thatboth eyes of each individual would have thesame retinal status was higher when one eyewas normal or had only slight retinopathy(Table 3). Among 62 eyes with proliferativeretinopathy, 42 (68%) had the same conditionin the fellow eye, five (8%) had preproliferative

TABLE2PREVALENCE OF HARD EXUDATES

WITH

EXUDATESNO. OF

CLINICAL DATA PATIENTS NO. %

Diabetes duration (yrs)

o to 10 169 15 911 to 20 120 42 3521 and more 79 30 38

Age at examination (yrs)

<29 46 4 930 to 49 96 22 2350 to 69 138 33 2470 and older 98 28 29

and 11 (18%) had background retinopathy, andfour (6%) had a normal fellow eye.

Twenty-three patients had opaque ocularmedia that precluded examination of the fun­dus (bilaterally in five subjects) and were exam­ined by ultrasonography. Twelve had changescompatible with proliferative retinopathy; inseven the fellow eye displayed clear media andproliferative retinopathy. Five subjects showedultrasonographic evidence of vitreous hemor­rhage or membranes and were classified ashaving background retinopathy. Six patientshad normal ultrasonograms and were classified

TABLE 3AGREEMENT BETWEEN FELLOW EYES

FELLOW EYE (%)TYPE OF PROLIFERATIVE

RETINOPATHY BETTER SAME WORSE RETINOPATHY'

Normal 0 96 4 1Background 6 86 8 5Preproliferative 29 50 21 21Proliferative 32 68 0 68

'Cases of proliferative retinopathy included in the "same" and

"worse" categories.

436 AMERICAN JOURNAL OF OPHTHALMOLOGY October, 1986

as normals (the fellow eyes had clear media andno retinopathy).

Discussion

The prevalence of diabetic retinopathy wasdetermined in a well-defined and stable popu­lation. The rate of migration turnover of thepopulation was only 3.4%.24 The use of a dou­ble control (hospital records and the prescrip­tions received by the pharmacies) made it likelythat all insulin-treated diabetic patients weretraced. 12 Only 17 of 385 patients (4.4%) did notparticipate, and these were elderly people(mean age, 75 years).

The prevalence of retinopathy was 47% andthat of proliferative retinopathy 13%. In a pre­vious study of the same population," allinsulin-treated patients with onset at 40 or lessyears of age were examined by fluoresceinangiography, and the prevalence of retinopa­thy was found to be 66% and that of prolifera­tive retinopathy was 18%. The correspondingfigures in this study were 56% and 18%, re­spectively. Thus, fluorescein angiography en­hanced the diagnosis of background retinopa­thy but not that of proliferative retinopathy.

Few epidemiologic studies on the prevalenceof diabetic retinopathy have been published.Reports from Australia.':" Denmark." Iceland,"and the United States"? showed large variationsin the prevalence of total (24% to 70%) andproliferative (4.5% to 22%) retinopathy, partlybecause they were not performed under thesame conditions. In addition, considerable dif­ferences exist as to the nonparticipating frac­tion of the study population (up to 20%), theannual migration rate of the population, theage distribution of the patients, dissimilaritiesin the treatment of diabetes, and genetic varia­tions affecting the diabetes prevalence of thepopulation (0.12% to 0.72%).

When we divided our study population intogroups of different ages at onset of diabetes,the highest prevalence of retinopathy wasamong patients with diabetes onset at 20 or lessyears of age. This was statistically significantby a simple logistic regression test. However,this test also yielded significant differenceswhen retinopathy was correlated to the dura­tion of diabetes. Patients with early onset ofdiabetes had also had diabetes the longest(Table 1). Obviously, there is a relationshipbetween age at onset and duration of diabetes(r = -0.44). Consequently, studying one ofthese variables requires the other to be taken

into consideration. By multiple logistic regres­sion analysis it appears that the differences inthe prevalence of retinopathy with differentages at onset of diabetes were not statisticallysignificant when duration was taken into ac­count (P > .2). However, when the relationshipbetween retinopathy and duration was ana­lyzed controlling for age at onset, for a higherprevalence of retinopathy was still found to berelated to a longer duration (P < .001). Thus,the duration of diabetes was the predominantfactor determining the prevalence of both totaland proliferative retinopathy, and age at onsetwas subordinate. These results support thereport of Constable and associates."

Among the groups of different ages at onsetof diabetes, there were some variations in theprevalence of retinopathy. When diabetes du­ration was less than ten years, the prevalenceof retinopathy was somewhat higher in pa­tients with onset between 41 and 60 years thanin other groups (Fig. 5). Such a tendency wasalso noted by Aiello and associates." whofound that in 67% of patients with backgroundretinopathy and a diabetes duration of lessthan ten years, the onset of diabetes was afterthe age of 40 years. This group probably includ­ed non-insulin-dependent patients whose realduration of diabetes may have been much long­er than the diagnosed one. Kahn and Bradley"also suggested that age is correlated to retinop­athy only when the duration of diabetes is lessthan ten years.

In the long-term, however, there is a uniformincrease in the prevalence of retinopathy re­gardless of the age at onset of diabetes (exceptafter the age of 60 years). All patients withjuvenile-onset diabetes presumably have in­sulin-dependent disease, whereas those withonsets between 41 and 60 years do not. Never­theless, after a known duration of 11 years ormore, both groups exhibited the same preva­lence of retinopathy. The highest prevalence ofproliferative retinopathy (55%) developed inthe group who were youngest at onset and whohad the longest duration of diabetes (19.7years). This observation was in accord withprevious studies." The results for patients withonsets after the age of 60 years were not conclu­sive; among these, few subjects had a longduration of diabetes and cataracts and senilitymade examination difficult.

Retinopathy with hard exudates correlated toduration of diabetes and the age of the pa­tients. Hard exudates occurred more often inthose over 60 years of age, a finding also notedby Klein and associates." This indicated thatfactors other than the duration of diabetes also

Vol. 102, No.4 Diabetic Retinopathy 437

influence retinal disease. The pathogeneticmechanisms are still speculative. A correlationbetween a higher prevalence of diabetic macu­lopathy and adult-onset diabetes has been re­ported. 5,13,27 This was reflected in our study asthe prevalence of hard exudates.

References

1. Heriot, W, J., Borger, J. P., Zimrnet, P., King,H., Taylor, R., and Raper, 1. R.: Diabetic retinopathyin a natural population. Aust. J. Ophthalmol. 11:175,1983.

2. Danielsen, R., [onasson, F., and Helgascn, T.:Prevalence of retinopathy and proteinuria in type 1diabetics in Iceland. Acta Med. Scand. 212:277, 1982.

3. Constable, I. J., Knuiman, M. W., Welborn,T. A., Cooper, R. 1., Stanton, K. M., McCann, V. J.,and Grose, G. c.: Assessing the risk of diabeticretinopathy. Am. J. Ophthalmol. 97:53, 1984.

4. Nielsen, N. V.: Diabetic retinopathy. I. Thecourse of retinopathy in insulin-treated diabetics. Aone year epidemiological cohort study of diabetesmellitus. The island of Falster, Denmark. Acta Oph­thalmol. 62:256, 1984.

5. Klein, R., Davis, M. D., Moss, S. E., Klein, B.,and DeMets, D. 1.: The Wisconsin epidemiologicstudy of diabetic retinopathy. A comparison of reti­nopathy in younger and older onset diabetic per­sons. In Vranic, M., Hollenberg, C. H., and Steiner,G. (eds.): Comparison of Type I and II Diabetes. NewYork, Plenum Press, 1985, pp. 321-335.

6. Klein, R., Klein, B. E. K., Moss, S. E., Davis,M. D., and DeMets, D. 1.: The Wisconsin epidemio­logic study of diabetic retinopathy. II. Prevalenceand risk of diabetic retinopathy when age at diagno­sis is less than 30 years. Arch. Ophthalmol. 102:520,1984.

7. : The Wisconsin epidemiologic study ofdiabetic retinopathy. III. Prevalence and risk of dia­betic retinopathy when age at diagnosis is 30 or moreyears. Arch. Ophthalmol. 102:527, 1984.

8. Mitchell, P.: The prevalence of diabetic retinop­athy. A study of 1300 diabetics from Newcastle andHunter Valley. Aust. J. Ophthalmol. 8:241, 1980.

9. [erneld, B., and Algvere, P.: The prevalence ofretinopathy in juvenile-onset diabetes mellitus. Afluorescein angiographic study. Acta Ophthalmol.62:617, 1984.

10. : Prevalence of retinopathy in diabetestreated with oral antihyperglycaemic agents. ActaOphthalmol. 63:535, 1985.

11. Bergman, U.: Utilization of antidiabetic drugsin the island of Gotland, Sweden. Agreement be­tween wholesale figures and prescription data. Eur.J. Clin. Pharmacol. 14:213, 1978.

12. Green, A., Hauge, M., Holm, N. V., andRasch, 1.: Epidemiological studies of diabetes melli­tus in Denmark. II. A prevalence study based oninsulin prescriptions. Diabetologia 20:468, 1981.

13. Aiello, 1. M., Rand, 1. I., Briones, J. c..Wafai, M. Z., and Sebestyen, J. G.: Diabetic retinop­athy in Joslin clinic patients with adult-onset diabe­tes. Ophthalmology 88:619,1981.

14. Sigelman, J.: Diabetic macular edema injuvenile- and adult-onset diabetes. Am. J. Ophthal­mol. 90:287, 1980.

15. Soler, N. G., Fritzgerald, M., Malins, J., andSummers, R.: Retinopathy at diagnosis of diabetes,with special reference to patients under 40 years ofage. Br. Med. J. 3:567, 1969.

16. Palmberg, P., Smith, M., Waltman, S., Krupin,T., Singer, P., Burgess, D., Wendtlant, T.,Achtenberg, J., Cryer, P., Santiago, J., White, N.,Kilo, C.; and Daughaday, W.: The natural history ofretinopathy in insulin-dependent juvenile-onset dia­betes. Ophthalmology 88:613, 1981.

17. Diabetic Retinopathy Study Research Group:Manual of Operations. Baltimore, Diabetic Retinopa­thy Coordinating Center, University of Maryland,1972, ch. 9.

18. Berkow, J. W.: Diabetic retinopathy. Int. Oph­thalmol. Clin. 17:89, 1977.

19. Murphy, R. P., and Patz, A.: The natural his­tory and management of non-proliferative diabeticretinopathy. In Little, H. 1., Patz, A., Jack, R. 1., andForsham P. H. (eds.): Diabetic Retinopathy. NewYork, Thieme-Stratton, 1983, pp. 225-241.

20. Diabetic Retinopathy Study Research Group:Photocoagulation treatment of proliferative diabeticretinopathy. The second report of Diabetic Retinopa­thy Study findings. Ophthalmology 85:82, 1978.

21. : Photocoagulation treatment of pro-liferative diabetic retinopathy. Clinical application ofDiabetic Retinopathy Study (DRS) findings. DRS Re­port No.8. Ophthalmology 88:583, 1981.

22. Jerneld, B., Algvere, P., and Singh, G.: Anultrasonographic study of diabetic vitreo-retinal dis­ease with low visual acuity. Acta Ophthalmol.58:193,1980.

23. Cox, D. R.: Analysis of binary data. London,Methuen, 1970, pp. 1-142.

24. Official Statistics of Sweden. Summary of VitalStatistics 1979-1981 by county. Stockholm, Statis­tiska Centralbyran, 1982, vol. 1, pp. 122-124.

25. Kahn, H. A., and Bradley, R. F.: Prevalence ofdiabetic retinopathy. Br. J. Ophthalmol. 59:345,1975.

26. Klein, R., Klein, B. E. K., Moss, S. E., Davis,M. D., and DeMets, D. 1.: The Wisconsin epidemio­logic study of diabetic retinopathy. IV. Diabetic mac­ular edema. Ophthalmology 91:1464, 1984.

27. Kohner, E. M.: The evolution and natural his­tory of diabetic retinopathy. Int. Ophthalmol. Clin.18:1, 1978.