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Risk Factors for Progression to Referable Diabetic Eye Disease in People With Diabetes Mellitus in Auckland, New Zealand: A 12-Year Retrospective Cohort Analysis

Hill, Sophie FRCOphth∗,||; Mullins, Peter MSc; Murphy, Rinki FRACP, PhD∗,‡; Schmiedel, Ole FRACP; Vaghefi, Ehsan PhD§; Ramke, Jacqueline MPH, PhD§,¶; Squirrell, David FRANZCO∗,||

Author Information
Asia-Pacific Journal of Ophthalmology: November-December 2021 - Volume 10 - Issue 6 - p 579-589
doi: 10.1097/APO.0000000000000464

Abstract

Diabetic retinopathy (DR) is one of the leading causes of blindness (<3/60 or less than 10-degree visual field around central fixation in the better-seeing eye1) in the working-age population, accounting for approximately 2.5%1 of global blindness in 2020 and 4.5%2 of blindness in Australasia. It has a significant detrimental effect on patients’ social and emotional welfare3 and it is well recognized that screening for, and where appropriate treating, DR can avoid sight loss, thus reducing working age disability and economic burden.4,5

Worldwide, multiple studies have examined the prevalence of DR and its associated risk factors in large populations of people living with diabetes. These include studies from New Zealand,6–9 Australia,10,11 UK,12,13 Europe,14 US,15 and Singapore.16 These studies have shown that between 65% and 79% of patients at the initial DR screening visit have no retinopathy8,11,12; 18%–35% of patients have non–sight-threatening retinopathy; and 0.4%–11% of patients have sight-threatening retinopathy detected at initial screening assessment.6,10,11,17 Independent risk factors for retinopathy grade at initial screening assessment include: higher baseline HbA1c/fasting glucose levels,7,8,11,14,16 longer duration of diabetes,10,12,14 treatment with insulin,10,12 the ethnicity of Indian and Pacific Peoples,8,16 age at diagnosis,14,17 Type 1 diabetes mellitus (T1DM),14,17 and higher diastolic blood pressure.14

In 2019, the resident population of New Zealand (NZ) was 4.92 million,18 of which 1,108,850 reside within the Auckland District Health Board (ADHB)19 and Counties Manukau District Health Board (CMDHB)20 catchments. An estimated 253,480 New Zealanders are living with diabetes mellitus (DM), and of these 67,917 currently reside within the area served by ADHB and CMDHB.21 The NZ diabetic retinal screening guidelines recommend that screening commences at the age of 10, or 2 to 5 years after the diagnosis of diabetes depending upon HbA1c, and every 1 to 2 years thereafter.

This study aimed to evaluate both the prevalence of any and referable retinopathy, and maculopathy in our population at the first screening visit, and the independent risk factors for progression to referable disease for people living with T1DM and Type 2 diabetes mellitus (T2DM) attending the retinal screening programs of ADHB and CMDHB, so that optimal retinal screening intervals specific to this unique multi-ethnic population could be determined.

MATERIALS AND METHODS

This retrospective cohort study uses anonymized data of all patients who attended for their first diabetic eye screening at ADHB and CMDHB between January 2006 and December 2018. The cohort, therefore, includes all individuals newly diagnosed with diabetes and referred to screening for the first time, and those who had been living with diabetes before enrolment and who might have been screened elsewhere in the country. The study adhered to the Declaration of Helsinki, with ethics approval obtained from ADHB (A+8335) and CMDHB (934) ethics committees. In NZ, DM is defined as HbA1c >50 mmol/mol on 2 separate occasions, physician diagnosed diabetes or the use of glucose-lowering medication. As part of routine care, at every retinal screening visit, all participants undergo a standardized assessment, which includes recording the current diabetes treatments, the latest HbA1c and demographic data including ethnicity. Diabetes treatments were categorized as insulin, oral hypoglycaemic agents (including acarbose, chlorpropamide, glibenclamide, gliclazide, glipizide, metformin, pioglitazone, vildagliptin dispensed at least once during 6 months before the index assessment), or diet. The HbA1c measurement was the most recent result recorded before baseline risk assessment, or, if none were available, up to 6 months post-baseline.

Smoking status, blood pressure, and renal function were not routinely collected, and these indices have not been included in the analysis. Persons aged 12 years or above with DM who were not under the care of the hospital eye service for DR-related reasons were required to be referred for screening. The screening service was provided with the individuals’ demographic and diagnostic information, including ethnicity,22 type of diabetes, HbA1c, self-reported hypertension, and date of diagnosis. For the purposes of investigating the associations of DR and ethnicity, the self-identified ethnicities were categorized according to the NZ level 1 classification. For statistical purposes, people who self-identified with more than 1 ethnicity were routinely classified to only 1 ethnicity in a defined prioritized order.22 However, a large Indian and Fijian-Indian community22 were identified within the Asian category, and for the purposes of analysis they were defined as Indian and separated from the Asian category for the data analysis. Very few people were categorized as Middle Eastern and they were excluded from the data analysis.

Retinal Screening Protocol

After an initial interview during which basic demographics were confirmed, all patients underwent an assessment of their best-corrected visual acuity, defined as best vision achieved with current glasses (if worn) or unaided if not, with and without pinhole. The patient was then photographed through undilated pupils. If an adequate fundus image could not be obtained, the patient was dilated with mydriatics and rephotographed. If an adequate image was still not obtained, they would be evaluated at the slitlamp by a trained optometrist who would then grade the retinopathy.

Retinal Photography and Diabetic Retinopathy Grading

All images were graded by reporting teams at ADHB and CMDHB using the NZ Ministry of Health (MoH) DR standard23 (Supplementary Table 1, https://links.lww.com/APJO/A121). This standard is based on the modified Airlie House Classification Scheme of the Early Treatment Diabetic Retinopathy Study (ETDRS),24 but with a higher level of differentiation between grades which range from R0–R5 and M0–M5 (Supplementary Table 1, https://links.lww.com/APJO/A121). The rescreen interval for each patient is determined by the worse grade (R or M) in the worst eye. To simplify the analysis of this large data set, the NZ retinopathy grades were truncated into R0–R3, and the maculopathy grades were truncated into M0–M3 (Supplementary Table 1, https://links.lww.com/APJO/A121). In this truncated grading system, either proliferative or severe non-proliferative DR (R3) and/or center-involving maculopathy (M3) were considered “referrable”.

Statistical Analysis

Characteristics of the study population and baseline retinopathy grades were described using means and standard deviation (SD) for continuous variables with percentages for categorical variables as appropriate. The continuous variables of age at diagnosis, HbA1c, and duration of diabetes were categorized. Age was divided into subgroups: age below 45 years, 45 to 65 years, and above 65 years. HbA1c was divided into subgroups: <65 mmol, 65 to 75 mmol, and >75 mmol. Duration of diabetes (from the date of first diagnosis) was subdivided into <6 years, 6 to 10 years, 11 to 15 years, and >15 years. Self-identified ethnicity was categorized as NZ Europeans, Ma¯ori, Pacific Peoples, Indians, Chinese/other Asians, Europeans, and others. For comparison, t tests and x2 tests were used respectively with a P value of <0.05 indicating statistical significance. As individuals entered and exited screening during different time points, a dynamic cohort design was used, and the cumulative and annual incidence of progression to any or referable retinopathy, from no retinopathy, mild non-proliferative diabetic retinopathy (NPDR), and moderate NPDR, at baseline for individuals with T1DM and T2DM was then derived using time intervals of 2, 4, 8, and 12 years from their first baseline screening event. This exercise was repeated for maculopathy. The mean screening interval for progression to referable DR and maculopathy, related to the baseline retinopathy status, was determined from interpolation of actuarial life tables. The mean screen intervals (years) for a 95% likelihood of remaining disease-free of any referable retinopathy and maculopathy were calculated. Logistic regression analyses were performed to assess the association of the routinely collected variables with retinopathy and maculopathy status for each type of DM. The hazard ratios and 95% confidence interval (CI) for each variable were calculated.

RESULTS

Cohort Characteristics

A total of 58,007 people living with diabetes attended at least 1 diabetic eye screening appointment at ADHB and CMDHB between 2006 and 2018; 2271 with T1DM and 55,736 with T2DM. This represents 85% of the estimated 67,917 people in the ADHB and CMHDB recorded on the Virtual Diabetes Register3. Figure 1 summarizes the processes by which patients’ data were recruited into the study.

FIGURE 1
FIGURE 1:
High-level overview of the data processes used to enroll patients’ data into this study.

At baseline screening, the overall prevalence of no retinopathy was 51.8% within the cohort of people with T1DM and 75% in the T2DM cohort. 62.2% of the cohort of people with T1DM and 78.1% of the cohort with T2DM had no maculopathy at baseline. Any DR within the cohort of people with T1DM was 48.2%, and of referable DR was 4.4%. In the cohort of people with T2DM, the overall prevalence of any DR at baseline screening was lower at 25%, and just 1.6% had referable retinopathy. The overall prevalence at baseline screening assessment of any maculopathy within the cohort of people with T1DM was 37.8%, and 4.8% had referable maculopathy. The overall prevalence of any maculopathy in the cohort of people with T2DM was again lower at 21.9%, and 2.8% had referable maculopathy.

The ethnicity of the population attending diabetic eye screening, stratified by type of DM and baseline DR and maculopathy grading is summarized in Figure 2 and Supplementary Table 2, https://links.lww.com/APJO/A121.

FIGURE 2
FIGURE 2:
Stacked bar graph representing disease severity at baseline screening by type of DM, disease grade, and ethnicity. DM indicates diabetes mellitus.

Regardless of diabetes type, Māori, Pacific Peoples, and people of Indian ethnicity presented with more advanced disease at baseline assessment compared to other groups. Pacific Peoples represented 9% of people with T1DM and yet represented 21.8% of those with R3 at baseline. Similar disparities were observed in Māori (8% in total; 16% R3) and the Indian population (4% in total and 17% R3).

Of those who attended DR screening, 41,786 individuals (75% of the population screened; 1689 with T1DM and 40,097 with T2DM) underwent 2 or more retinal photo screening events between 2006 and 2018, and the data from these individuals were used in the progression analysis. The baseline retinopathy and maculopathy combinations of this group are summarized in Table 1. The baseline characteristics for these individuals, by the individual retinopathy and maculopathy combinations, are summarized in Table 2A and B.

TABLE 1 - Grade Combinations at Baseline Screen of Those 41,786 Patients Who Had 2 or More Attendances by Type of Diabetes
Grade Combinations
R0M0 R1M0 R1M1 R1M2 R1M3 R2M0 R2M1 R2M2 R2M3 R3M0 R3M1 R3M2 R3M3 Total
Type 1 DM 862 220 490 30 21 0 19 5 3 6 17 2 11 1683
51.5% 13.1% 29.2% 1.8% 1.1% 0.0% 1.1% 0.3% 0.1% 0.3% 0.7% 0.2% 0.6%
Type 2 DM 28544 3349 7292 238 258 15 151 50 61 13 40 18 68 40097
71.2% 8.4% 18.2% 0.6% 0.6% 0.0% 0.4% 0.1% 0.2% 0.0% 0.1% 0.0% 0.2%
Total 29399 3562 7784 268 287 15 170 55 67 19 53 22 78 41786
70.4% 8.5% 18.6% 0.6% 0.7% 0.0% 0.4% 0.1% 0.1% 0.0% 0.1% 0.1% 0.2%
DM indicates diabetes mellitus.

TABLE 2 - A. Baseline Characteristics for Individuals With T1DM Who Underwent 2 or More Screening Assessments by Individual Retinopathy and Maculopathy Grade
Type 1 DM Grade R0 (N = 910) Grade R1 (N = 714) Grade R2 (N = 25) Grade R3 (N = 31) P value Grade M0 (N = 1090) Grade M1 (N = 538) Grade M2 (N = 40) Grade M3 (N = 30)
Age median y (IQR) 29.0 (15.0, 43.0) 32.0 (22.0,47.0) 35.0 (29.0, 53.0) 41.0 (31.0, 55.0) <.0001 28.0 (15.0, 44.0) 33.0 (24.0, 47.0) 43.0 (32.0, 56.0) 38.0 (31.0, 53.0)
Diabetes duration median y (IQR) 5.0 (3.0, 10.0) 13.0 (6.0, 21.0) 16.0 (10.0, 24.0) 21.0 (14.0, 35.0) <.0001 6.0 (3.0, 11.0) 13.0 (6.0, 22.0) 20.0 (15.0, 25.0) 18.0 (10.0, 27.0)
Age at diagnosis median y (IQR) 20.5 (10.0, 33.0) 17.0 (10.0, 28.0) 19.0 (12.0, 33.0) 18.0 (11.0, 23.0) 0.0254 19.0 (9.0, 32.0) 17.0 (11.0, 28.0) 22.0 (12.5, 33.0) 16.5 (9.0, 29.0)
Follow-up duration median y (range) 62.0 (3.0–159.0) 39.0 (0.0–123.0) 12.0 (0.0–77.0) n/a <.0001 59.0 (0.0–159.0) 37.0 (0.0–119.0) 18.0 (0.0–108.0) n/a
Screening visits median (range) 4.0 (2.0–13.0) 4.0 (2.0–13.0) 2.0 (2.0–11.0) 3.0 (2.0–6.0) <.0001 4.0 (2.0–13.0) 4.0 (2.0–13.0) 3.0 (2.0–10.0) 3.0 (2.0–9.0)
Males n (%) 505 (30.1%) 373 (22.2%) 15 (0.9%) 14 (45.2%) 0.3848 593 (35.3%) 278 (16.5%) 17 (1.0%) 19 (63.3%)
Females n (%) 404 (44.4%) 341 (47.8%) 10 (40.0%) 17 (54.8%) 0.3663 496 (45.5%) 243 (46.6%) 22 (56.4%) 11 (36.7%)
DM indicates diabetes mellitus.
TABLE 2. B. Baseline Characteristics for Individuals With T2DM Who Underwent 2 or More Screening Assessments by Individual Retinopathy and Maculopathy Grade
Type 2 DM Grade R0 (N = 30,621) Grade R1 (N = 9060) Grade R2 (N = 277) Grade R3 (N = 139) P value Grade M0 (N = 31,921) Grade M1 (N = 7483) Grade M2 (N = 306) Grade M3 (N = 387) P value
Age median y (IQR) 61.0 (53.0, 70.0) 59.0 (50.0, 68.0) 61.0 (51.0, 69.0) 62.0 (50.0, 71.0) <.0001 62.0 (53.0, 70.0) 57.0 (48.5, 67.0) 59.0 (52.0, 67.0) 60.0 (51.0, 68.0) <.0001
Diabetes duration median y (IQR) 2.0 (1.0, 6.0) 5.0 (1.0, 10.0) 10.0 (4.0, 16.0) 14.0 (6.0, 20.0) <.0001 2.0 (1.0, 6.0) 4.0 (1.0, 9.0) 9.0 (3.0, 16.0) 8.0 (3.0, 16.0) <.0001
Age at diagnosis median y (IQR) 57.0 (49.0, 66.0) 52.0 (43.0, 61.0) 49.0 (42.0, 56.0) 47.0 (39.0, 54,0) <.0001 57.0 (49.0, 66.0) 51.0 (43.0, 60.0) 49.0 (41.0, 57.0) 49.0 (42.0, 57.0) <.0001
Follow-up duration median y (range) 61.0 (0.0–176.0) 36.0 (0.0–146.0) 12.0 (0.0–105.0) n/a <.0001 59.0 (0.0–176.0) 37.0 (0.0–146.0) 22.5 (0.0–114.0) n/a <.0001
Screening visits median (range) 3.0 (2.0–16.0) 3.0 (2.0–15.0) 2.0 (2.0–13.0) 2.0 (2.0–13.0) <.0001 3.0 (2.0–16.0) 3.0 (2.0–15.0) 3.0 (2.0–15.0) 2.0 (2.0, 13.0) <.0001
Males n (%) 15789 (51.6%) 4971 (54.9%) 152 (54.9%) 78 (56.1%) <.0001 16516 (51.7%) 4089 (54.6%) 163 (53.3%) 222 (57.4%) <.0001
Females n (%) 14827 (48.4%) 4089 (45.1%) 125 (45.1%) 61 (43.9%) <.0001 15400 (48.2%) 3394 (45.4%) 143 (46.7%) 165 (42.6%) <.0001
Treatment at baseline
 Diet alone 5218 (17.0%) 1206 (13.3%) 10 (3.6%) 2 (3.6%) <.0001 5456 (17.1%) 947 (12.7%) 18 (5.9%) 15 (3.9%) <.0001
 No glucose-lowering therapy 18479 (60.3%) 7304 (80.6%) 251 (90.6%) 106 (76.3%) <.0001 19486 (61.0%) 6053 (80.9%) 266 (86.9%) 335 (86.6%) <.0001
 Insulin 1281 (4.2%) 1457 (15.9%) 93 (33.6%) 58 (41.7%) <.0001 1510 (4.7%) 1173 (15.7%) 85 (27.8%) 121 (31.3%) <.0001
DM indicates diabetes mellitus.
Follow-up is from first assessment to achievement of grade R3 or M3, or last assessment (months).

A number of individuals with T1DM (n = 61) and T2DM (n = 526) had referable disease at presentation (≥R3, M3). Although they were referred to ophthalmologists, they did not attend the appointment and were therefore re-referred back to screening a few years later. Consequently, these individuals appear in the dataset describing the group which had 2 or more attendances in screening, but their data were not used in the progression analyses. The mean number of assessments per individual was 3.8 in the T1DM cohort and 3.1 in the T2DM cohort. The rescreen interval ranged from 6 months to >6 years. 96% of the study population had T2DM, 11.9% of which were treated with insulin. The mean HbA1c at initial screen was higher in those with T1DM (72.0 mmol/mol) compared to those with T2DM (62.7 mmol/mol). The mean duration of diabetes at the first screening was 12.8 years and 5.9 years for the T1DM and T2DM cohorts, respectively. Longer duration of DM in both cohorts and higher frequency of insulin use in the T2DM cohort was associated with increased retinopathy grade at baseline.

Progression of Diabetic Retinopathy and Screening and Assessment Intervals

Of those individuals with no retinopathy at baseline, 75% of people with T1DM went on to develop any retinopathy during follow-up, compared to only 47% with T2DM. For both T1DM and T2DM, the likelihood of progression was significantly greater if both eyes of an individual had observable retinopathy in both eyes, compared to observable retinopathy in just 1 eye (Table 3A-B). Mean screen interval in years for a 95% likelihood of remaining free of any retinopathy in those with T1DM and no retinopathy at initial screen was 3.2 years [95% confidence interval (CI), 3.0–3.4 years], compared to 4.2 years (95% CI, 4.2–4.3 years) for those with T2DM. The rate of developing referable retinopathy (R3) from no retinopathy was low in both groups, with only 4.2% and 1.7% progressing in the T1DM and T2DM cohorts respectively. Mean screen interval in years for a 95% likelihood of remaining free of referable retinopathy from no retinopathy at initial screen was 6.1 years (95% CI, 1.1–13.2 years) for patients with T1DM, compared to 7.3 years (95% CI, 0.4–13.5 years) in those with T2DM. Regardless of the type of DM, individuals with a higher baseline retinopathy and a higher HbA1c were more likely to progress to referable retinopathy (Table 3A-B, Fig. 3A-B, and Table 4) and referable maculopathy (Fig. 3C-D and Table 4).

TABLE 3 - A. Percentage of Individuals With T1DM Experiencing DR Progression According to Number of Eyes With Observable Retinopathy at Baseline (Where 0 = No Retinopathy in Either Eye, 1 = Observable Retinopathy Only in 1 Eye, 2 = Any Retinopathy in Both Eyes)
Final retinopathy grade
No. eyes with retinopathy at baseline R0 R1 R2 R3 Total % Progression to R3 % Progression to any retinopathy
0 217 587 25 36 865 4.2% 74.9%
1 251 11 6 268 2.2%
2 420 58 69 547 12.6%
DR indicates diabetic retinopathy; TIDM, Type 1 diabetes mellitus.
Least-significant difference comparisons (95% confidence interval) of the proportions who progress to R3. Compare class 0 to class 1: (-0.046, 0.008), no significant difference; class 0 to class 2: (0.047, 0.122), P < 0.001. Progression class 1 to class 2: (0.063, 0.144), P < 0.001 [Mantel Haenszel]
TABLE 3. B. Percentage of Individuals With T2DM Experiencing DR Progression According to Number of Eyes With Observable Retinopathy at Baseline (Where 0 = No Retinopathy in Either Eye, 1 = Observable Retinopathy Only in 1 Eye, 2 = Any Retinopathy in Both Eyes)
Final retinopathy grade
No. eyes with retinopathy at baseline R0 R1 R2 R3 Total % Progression to R3 % Progression to any retinopathy
0 14975 12468 629 472 28544 1.7% 47.5%
1 5640 132 70 5842 1.2%
2 4497 732 484 5713 8.5%
DR indicates diabetic retinopathy; T2DM, Type 2 diabetes mellitus.
Least-significant difference comparisons (95% confidence interval) of the proportions who progress to R3. Compare class 0 to class 1: (–0.008, –0.001), P < 0.001; class 0 to class 2: (0.053, 0.07), P < 0.001; class 1 to class 2: (0.057, 0.075), P < 0.001 [Mantel Haenszel]

FIGURE 3
FIGURE 3:
A, Survival to referrable retinopathy R3 (months), in individuals with T1DM by grade of retinopathy at the first screen (R0, R1, R2).Harrell's Concordance Statistic 0.7493. B, Survival to referrable retinopathy R3 (months), in individuals with T2DM by grade of retinopathy at the first screen (R0, R1, R2).Harrell's Concordance Statistic 0.7907. C, Survival to referrable maculopathy M3 (months), in individuals with T1DM by grade of maculopathy at the first screen (M0, M1, M2). D, Survival to referrable maculopathy M3 (months), in individuals with T2DM by grade of maculopathy at first screen (M0, M1, M2). T1DM indicates Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus.
TABLE 4 - Mean Screen Intervals in Years for a 95% Likelihood of Remaining Free of Any and Referable Retinopathy or Maculopathy Based on Initial Screening Grade
Type 1 DM Type 2 DM
Survival Type Mean Duration Years (95% CI) N (%) R0 910 patients M0 1090 patients Mean Duration Years (95% CI) N (%) R0 30,621 patients M0 31,921 patients
No retinopathy to any retinopathy 3.2 (3.0–3.4) 4.2 (4.2–4.3)
640/910 (70%) 11887/30621 (39%)
No retinopathy to referable retinopathy 6.1 (1.1–13.2) 7.3 (0.4–13.5)
38/910 (4.2%) 487/30621 (1.6%)
Mild retinopathy to referable retinopathy 3.8 (0.6–9.3) 3.7 (0.3–10.5)
30/714 (4.2%) 319/9060 (3.5%)
Moderate retinopathy to referable retinopathy 1.8 (0.5–4.5) 2.5 (0.3–10.2)
12/25 (48%) 81/277 (29%)
No maculopathy to any maculopathy 3.3 (3.2–3.5) 4.0 (4.0–4.1)
708/1090 (65%) 12153/31921 (38%)
No maculopathy to referable maculopathy 5.5 (0.9–13.2) 5.8 (0.3–13.4)
108/1090 (9.9%) 1611/31921 (5.0%)
Mild maculopathy to referable maculopathy 3.1 (0.3–9.1) 2.9 (0.2–9.6)
809/538 (15%) 813/7483 (11%)
Moderate maculopathy to referable maculopathy 1.6 (0.3–5.5) 2.2 (0.5–8.0)
14/40 (35%) 84/306 (27%)
CI indicates confidence interval; DM, diabetes mellitus.

Progression of Diabetic Maculopathy and Screening and Assessment Intervals

Of those individuals with no maculopathy at baseline 64.9%, individuals with T1DM went on to develop any maculopathy, compared to only 38% of those with T2DM. The mean screen interval in years for a 95% likelihood of remaining free of any maculopathy for individuals with T1DM and no maculopathy at baseline was 3.3 years (95% CI, 3.2–3.5), compared to 4.0 years (95% CI, 4.0–4.1) for those with T2DM. In both T1DM and T2DM, the rate of progression of maculopathy was faster than that of retinopathy. The mean screen interval in years for a 95% likelihood of remaining free of referable maculopathy in those with no maculopathy at baseline was 5.5 years (95% CI, 0.9–13.2) in those with T1DM and 5.8 years (95% CI, 0.3–13.4) in those with T2DM (Table 4).

Table 5 shows the estimated annual and cumulative incidence of any and referable diabetic maculopathy from no maculopathy at baseline assessment. The cumulative incidence rates for any maculopathy rose progressively in both cohorts. Whilst the absolute values were at all time points higher in individuals with T1DM, the rate of increase was more rapid in the cohort with T2DM. The cumulative incidence rates for referable maculopathy also increased progressively with time from baseline assessment in both cohorts. Again, whilst the absolute values were at all time points higher in individuals with T1DM, the rate of increase was slightly more rapid in those with T2DM. Regardless of the type of DM, individuals with a higher baseline maculopathy and a higher HbA1c were more likely to progress to referable maculopathy.

TABLE 5 - Cumulative and Annual Incidence of Progression (Per 1000 People) to Any or Referable Retinopathy, From No Retinopathy at Baseline Assessment and Any or Referable Maculopathy, From No Maculopathy at Baseline Assessment in Individuals With T1DM and T2DM
Any retinopathy Referable retinopathy Any retinopathy Referable retinopathy
Type 1 DM Type 1 DM Type 2 DM Type 2 DM
Time from baseline screening Annual Incidence (95% CI) Cumulative incidence (95% CI) Annual Incidence (95% CI) Cumulative incidence (95% CI) Annual Incidence (95% CI) Cumulative incidence (95% CI) Annual Incidence (95% CI) Cumulative incidence (95% CI)
2 y 275 (245.7,305.3) 262 (233.0,290.1) 3.5 (0.8,9.6) 3.3 (0.7,9.3) 48 (45.2,50.0 46 (43.7,48.4) 0.6 (0.4,0.9) 0.6 (0.3,0.9)
4 y 402 (360.4,443.3) 499 (466.4,531.4) 12 (3.7,20.0) 12 (5.0,19.2) 206 (200.8, 211.0) 208 (203.3, 212.4) 2.2 (1.6,2.8) 2.4 (1.8,2.9)
8 y 370 (279.3,461.4) 671 (640.9,701.9) 33 (14.8,51.9) 32 (20.5,43.3) 197 (188.5, 206.2) 347 (341.3,351.9) 9.4 (7.6,11.2) 8.9 (7.9,10.0)
12 y 516 (267.3,764.9) 700 (670.2,729.8) 35 (24.2,48.4) 41 (27.8,53.5) 314 (288.4, 340.1) 387 (381.2,392.1) 41 (32.3,48.8) 15 (14.0,16.8)
Any maculopathy Referable maculopathy Any maculopathy Referable maculopathy
Type 1 DM Type 1 DM Type 2 DM Type 2 DM
Time from baseline screening Annual Incidence (95% CI) Cumulative incidence (95% CI) Annual Incidence (95% CI) Cumulative incidence (95% CI) Annual Incidence (95% CI) Cumulative incidence (95% CI) Annual Incidence (95% CI) Cumulative incidence (95% CI)
2 y 222 (196.9, 24.8) 209 (185.0, 233.3) 13 (5.9, 19.8) 12 (5.5, 18.4) 65 (61.8, 67.3) 62 (59.6, 64.9) 3.7 (3.1, 4.4) 3.6 (2.9, 4.3)
4 y 382 (345.2, 418.9 443 (413.6, 472.6) 33 (20.3, 45.0) 36 (24.8, 46.8) 204 (199.3, 209.4) 217 (212.8, 221.8) 16 (14.1, 172) 16 (14.5, 17.3)
8 y 385 (301.0, 468.2) 617 (588.6, 646.3) 53 (31.5, 74.7) 75 (59.6, 90.9) 187 (178.5, 196.1) 347 (341.7, 352.2) 26 (22.7, 28.5) 37 (35.2, 39.4)
12 y 560 (284.8, 835.2) 648 (619.3, 676.1) 74 (4.2, 143.9) 97 (79.7, 114.8) 269 (243.3, 295.1) 379 (373.9, 384.6) 67 (56.4, 77.5) 50 (47.3, 52.1)
Data are incidence (95% confidence interval) per 1000 people.

Independent Risk Factors for Prediction of Retinopathy and Maculopathy Progression

Table 6 shows the effects of independent hazards on the risk of the study participants progressing to referable retinopathy and maculopathy. These risk factors were different for the cohort of individuals with T1DM (baseline grade, HbA1c, duration of diabetes), compared to those with T2DM (baseline grade, HbA1c, duration of diabetes, insulin use, older age at diagnosis). They were also different for retinopathy (baseline grade, HbA1c, duration of diabetes, and in addition for T2DM: older age at diagnosis for T2DM) and maculopathy (baseline grade, HbA1c, duration of diabetes, and in addition for T2DM: older age at diagnosis, Asian ethnicity, insulin use).

TABLE 6 - Cox Proportional Hazards Analysis Relating Independent Variables to Development of Referable Retinopathy and Referable Maculopathy in T1DM and T2DM
Referable Retinopathy Referable Maculopathy
Type 1 DM Type 1 DM
Contrast Hazard Ratio 95% Confidence Interval P value Hazard Ratio 95% Confidence Interval P value
Baseline grade 0 vs 1 1.5 0.9, 2.4 0.15 1.9 1.4, 2.7 <.0001
Baseline grade 0 vs 2 32.4 15.6, 67.7 <.0001 5.3 2.9, 9.7 <.0001
Age (y) 45–64 0.3 0.1, 0.6 0.002 0.7 0.5, 1.0 0.049
Age (y) >=65 1.3 0.5, 3.3 0.63 0.6 0.3, 1.2 0.13
HbA1c (mmol) 65 –75 1.9 0.8, 4.3 0.13 1.0 0.7, 1.5 0.92
HbA1c (mmol) >75 6.7 3.3, 3.9 <.0001 2.1 1.5, 3.0 <.0001
Duration of diabetes (y) 6–10 2.3 1.2, 4.3 0.008 1.6 1.0, 2.7 0.04
Duration of diabetes (y) 11–15 2.7 1.3, 5.7 0.011 4.8 3.1, 7.6 <.0001
Duration of diabetes (y) >15 2.4 1.1, 4.9 0.020 3.4 2.2, 5.4 <.0001
Referable Retinopathy Referable Maculopathy
Type 2 DM Type 2 DM
Baseline grade 0 vs 1 4.1 3.5, 5.0 <.0001 3.4 3.1, 3.8 <.0001
Baseline grade 0 vs 2 31.3 23.8, 41.2 <.0001 8.8 7.0, 11.1 <.0001
Ethnicity Māori vs NZ Europeans 1.3 0.7, 2.6 0.45 1.0 0.6, 1.5 0.80
Ethnicity Other Polynesians vs NZ Europeans 1.6 0.8, 3.1 0.16 1.2 0.8, 1.8 0.45
Ethnicity Indians/Fiji Indians vs NZ Europeans 0.75 0.2, 2.7 0.67 1.7 1.08, 3.1 0.06
Ethnicity Asians vs NZ Europeans 1.1 0.6, 2.1 0.81 1.5 1.0, 2.3 0.03
Ethnicity Others vs NZ Europeans 0.6 0.22, 2.3 0.50 1.3 0.7, 2.3 0.35
Insulin Use 1.1 0.9, 1.3 0.37 1.2 1.1, 1.4 0.0006
Age (y) 45–64 0.6 0.5, 0.7 <.0001 0.9 0.8, 1.0 0.089
Age (y) >=65 0.4 0.3, 0.5 <.0001 0.6 0.5, 0.7 <.0001
HbA1c (mmol) 65–75 2.6 2.0, 3.2 <.0001 2.1 1.8, 2.3 <.0001
HbA1c (mmol) >75 6.9 5.8, 8.2 <.0001 3.9 3.6, 4.3 <.0001
Duration of diabetes (y) 6–10 1.7 1.5, 2.1 <.0001 1.7 1.6, 1.9 <.0001
Duration of diabetes (y) 11–15 2.3 1.9, 2.8 <.0001 2.1 1.8, 2.4 <.0001
Duration of diabetes (y) >15 2.5 2.0, 3.2 <.0001 2.3 2.0, 2.6 <.0001
DM indicates diabetes mellitus.

Regardless of the type of disease, the most significant risk factor for disease progression was the grade of retinopathy (HR baseline grade R0 v R2: 32.4 T1DM, 31.3 T2DM) or maculopathy (HR baseline grade M0 v M2: 5.3 T1DM, 8.8 T2DM) at initial assessment. Poor glycemic control also had a significant impact on progression of retinopathy (HR HbA1c >75 mmol v HbA1c <64 mmol: 6.7 T1DM, 6.9 T2DM) and maculopathy (HR HbA1c >75 mmol v HbA1c <64 mmol: 2.1 T1DM, 3.9 T2DM), as did duration of disease.

Individuals with T2DM, insulin use, and Asian ethnicity were associated with a higher risk of progression to referable maculopathy. In individuals with T2DM, diagnosis at age over 65 years was protective for the development of retinopathy and maculopathy. We discovered that self-reported hypertension was only reliably recorded in the ADHB cohort. Initial analysis revealed that, after correcting for other risk factors, self-reported hypertension was not a significant risk factor for progression of retinopathy (HR 1.2, P = 0.7).

Due to the lack of data in the CMDHB dataset and the significant logistic barriers involved in collecting the hypertensive data from the CMDHB dataset, self-reported hypertension was dropped from the final analysis.

DISCUSSION

Prevalence and Incidence

In the multi-ethnic population studied, the prevalence of referable DR (severe and proliferative DR as defined by the NZ MoH23) in individuals with T1DM was 4.4%, and in people with T2DM was 1.6%. The prevalence of referable maculopathy in individuals with T1DM was 4.8%, and in individuals with T2DM was 2.8%. Although differences in study methodologies, population characteristics, and the classification of DR make direct comparisons difficult, the prevalence rates observed in our study broadly match other published data on the prevalence of DR both in NZ and globally, where prevalence rates of sight-threatening retinopathy and maculopathy of 1.8–3.1%10,12,13 and 0.4–11%10–13,25 respectively have been reported. Consistent with other published data,8,26–28 we found that the prevalence of both any retinopathy and referable retinopathy at the first screening visit was higher in individuals with T1DM compared to those with T2DM.

To date, most global studies reporting on DR are predominantly drawn from Caucasian populations.29 Auckland has a high proportion of Māori, Pacific Peoples, and South Asian populations relative to other parts of NZ, and these groups are more likely to have diabetes, compared to other New Zealanders.12,13 We found that the prevalence of more severe retinopathy and maculopathy at the first screening visit was higher in the Māori, Pacific Peoples, and Indian groups, compared to other ethnicities. A small number of studies looking at ethnicity and DR also report a similar increased prevalence of disease in Asians and Pacific Peoples.6,8,30,31

Some of the heterogeneity in the prevalence of retinopathy at the first retinopathy screening assessment could be due to the extent of population screening for Type 2 diabetes, as screen-detected cases are unlikely to have had sufficient time to develop microvascular complications. 72% of our screened population underwent 2 or more screening assessments during the 12 years of this study. This falls short of the MoH's aspiration that 90% of people living with diabetes should be screened at least every 2 years.23 The reasons for nonattendance were not specifically examined in this project, but it is recognized that 40% of people living with diabetes are currently not being screened regularly in NZ, with Māori, Pacific Peoples, and those in rural areas being over-represented in these statistics.23 As expected, the annual and cumulative incidence of any and referable retinopathy and maculopathy increased with time from the baseline assessment. Detailed comparison with other published data is complicated by the lack of consistency in the reporting timeframes used, but the cumulative incidence of referable retinopathy and maculopathy per 1000 people at 4 and 8 years with T1DM and T2DM was broadly similar to the published data.13

In line with the published data,14,26,32 we found that a higher grade of retinopathy or maculopathy at baseline assessment was the largest, single most important hazard predicting the risk of progression to referable retinopathy or maculopathy in individuals with T1DM and T2DM. This influence was marginally stronger for those with T2DM compared to T1DM. We also found that the hazard of progressing to both referable retinopathy and maculopathy was significantly higher in individuals with a longer duration of diabetes.10–14,33 As reported previously,26 this influence was again higher in those individuals with T1DM, compared to those with T2DM at any given disease duration. The relationship between glycemic control and the risk of microvascular complications in both T1DM and T2DM is well established, and it is well recognized that a high HbA1c is a significant risk factor for the progression of DR.8,11,14,28,34–37 Our data confirm that a higher HbA1c at baseline increased the hazard of progression to referable retinopathy and maculopathy regardless of the type of DM. Higher cumulative HbA1c is also likely to be a significant risk factor for progression, although this was not available in this dataset. In both T1DM and T2DM, the greatest effect (HR 6.7 for T1DM and HR 6.9 for T2DM) was observed on referable retinopathy in patients with an HbA1c levels >75 mmol. Higher HbA1c also confers an increased hazard of progressing to referable maculopathy, and this effect was more marked in those with T2DM compared to those with T1DM (HR 3.9 v 2.1).

The association between insulin use in T2DM and progression of diabetic retinopathy has previously been described,12,13,26,38 but in previous studies, maculopathy and retinopathy have been frequently analyzed as a single disease. Our results suggested that insulin use in individuals with T2DM was associated with a significantly increased risk of progression to referable maculopathy (HR 1.2, P = 0.0006) but not retinopathy. Whilst this discrepancy needs to be confirmed by other studies, the Blue Mountains eye study also reported that both maculopathy and retinopathy were more prevalent in individuals with T2DM treated with insulin.10

We observed that in the cohort of individuals with T2DM, an older age (above 65 years) at the first screening assessment was associated with a reduced risk of progression to referable retinopathy and maculopathy (HR 0.39 and 0.58). Thomas et al13 reported a similar finding in individuals with T2DM, but the evidence for the effect of age on disease progression was unclear with some studies reporting greater odds of having any degree of DR with increasing age in individuals with T2DM,12 while others stated that age had no effect on disease progression.34

Compared to other ethnicities, Māori, Pacific Peoples, and Indians present with worse retinopathy at first contact with the screening service, yet the relationship between DR progression and ethnicity remains unclear. Consistent with previously published data from NZ,8 we found that with the exception of a slight increased risk of maculopathy progression in Asians with T2DM, in the presence of other risk factors, ethnicity had no significant association with the risk of progression to referable retinopathy or maculopathy. This suggests that factors other than ethnicity, such as delayed diagnosis of diabetes, delayed referral or uptake of retinal screening, and worse diabetes control are the main drivers for poorer outcomes in peoples in these groups.

Screening/Assessment Intervals

Actuarial life tables allow us to predict the optimum screening intervals for our study population. While existing cohort studies which used “sight-threatening disease” cannot be directly compared with the outcome “referable disease” used in this study, our results are broadly in agreement with other published data for patients with T1DM and T2DM.39 A systematic review of DR screening intervals found that in all of the 6 studies reviewed, the screening interval for T1DM/T2DM patients with no detectable diabetic retinopathy at baseline could be safely extended to 2 years or beyond.40 More recently, the 10-year cohort OPHDIAT study reported that the safe screening interval for patients without DR at the first examination for T1DM and T2DM was 2.2 (95% CI, 2.0–2.4) and 3.0 (2.9–3.1) years, respectively.41 In a subgroup of low-risk patients with Type 2 DM, the safe screening interval can probably be extended out further to 4 years.41,42 Our findings support these recommendations. Our data suggest that for our study population, screening intervals for individuals with T1DM with no retinopathy at baseline and no risk factors (no retinopathy/ maculopathy, HbA1c <65 mmol, duration of disease <6 years) can be safely extended to at least 3 years, whilst those living with T2DM with no risk factors (no retinopathy/maculopathy, HbA1c <65 mmol, duration of disease <6 years, age above 65 at diagnosis, not requiring insulin) can be safely extended to beyond 5 years. Whilst there is a risk that adopting such a long duration between screening assessments may affect rescreen attendance, a recent Swedish study found that extending treatment intervals to 36 months was not only safe but did not adversely affect attendance rates.43 Whilst further work is required to validate this finding, our data also support a rescreen interval of up to 3 years in low-risk patients.

Strengths and Limitations

Although the NZ MoH does not keep a register of people living with diabetes, the Virtual Diabetes Register (VDR)21 gives an estimate of the prevalence of diabetes in NZ, broken down by the District Health Boards and ethnicity. Comparison of the relative proportions of people living with diabetes in our cohort categorized by ethnicity is similar to that reported in the VDR (Māori 12%, Pacific Peoples 34%, Indian 21%, European/others 37%21). We are therefore confident that our data are representative of the wider population of people living with diabetes in the ADHB and CMDHB catchments. The main strengths of this study are the large size of the study population that underwent systematic screening, the unique ethnic composition of the population, and the long duration of follow-up. In our analysis, we examined data from people living with T1DM and T2DM separately and differentiated between retinopathy and maculopathy outcomes. This enabled greater distinction in the identification of risk factors for disease progression in both cohorts. Our study population represents the diverse ethnic population within NZ, providing greater insight into the progression of diabetic eye disease among different ethnic groups.

The main limitations of this study are the lack of information for patients’ blood pressure, lipid levels, smoking, and other microvascular complications such as proteinuria or estimated glomerular filtration rate measurements.26 Significant variations in the strength and consistency of these parameters as risk factors for progression have been reported.31 Although models designed to predict progression of retinopathy in patients with DM often include blood pressure,29,44 the results from large prospective studies have failed to demonstrate that hypertension is linked to the progression of DR. The UK Prospective Diabetes Study (UKPDS) reported that whilst hypertension was a risk for incident DR in T2DM, it may not contribute to the risk of progression in those with established retinopathy.45 The ACCORD study likewise reported that intensive blood pressure control did not reduce the rate of progression of established diabetic retinopathy.37 As smoking habit was inconsistently collected, we could not assess the impact of smoking on either the incidence or progression of DR in our cohort. However, other published data45,46 suggest that smoking is not associated with DR progression, and it is, therefore, unlikely that this omission will have any significant impact on our findings. It is now recognized that, at least in patients with T2DM, fluctuations in glycemic control may be as important as actual HbA1c for the progression of DR.47 As the recording of an individual's HbA1c on our database was linked to attendance, our data on HbA1c is not necessarily a reflection of the patient's glycemic profile, and thus we cannot assess the impact of glycemic variability on the progression of DR in our cohort. Finally, whilst it is well recognized that screening uptake is inversely related to socioeconomic class,31,48,49 as we did not record socioeconomic data in this study, we were unable to determine whether there was an association between socioeconomic class and either the incidence of DR or the progression of retinopathy.

CONCLUSIONS

Prevalence of referable retinopathy and maculopathy at baseline assessment in our screening population was comparable to previously reported data. The cumulative incidence of referable retinopathy and maculopathy was low in individuals with no disease at baseline regardless of DM type. The key risk factors identified for progression to referable retinopathy and maculopathy in individuals with T1DM and T2DM were higher retinopathy or maculopathy grade at baseline assessment, higher HbA1c, and longer duration of diabetes. Indian, Māori, and Pacific Peoples presented with higher grades of retinopathy and maculopathy at baseline screening, and they were at higher risk of progressing to advanced disease compared to NZ Europeans. However, when all other risk factors were considered, ethnicity was not a significant risk factor for progression. The only population group for which ethnicity was associated with more rapid disease progression was Chinese/other Asians, and then only for maculopathy.

Our findings support the lengthening of the screening intervals for people with no or mild diabetic eye disease at baseline screening. If implemented appropriately, this could reduce the cost of screening services, enabling existing services to focus on patients with the highest need for interventions, at the same time reducing the number of clinical appointments for people living with diabetes.

Acknowledgements

This study acknowledge the contribution of Stephanie Emma, Diabetic Retinopathy Screening Lead at CMDHB and Jyoti Unmesh, Data Analyst, Adult Medical Services & Adult Community and Long-Term Conditions, ADHB.

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Keywords:

Diabetes mellitus; maculopathy; prevalence; retinopathy; risk factors

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